AU2009319123B2 - Arylcyclohexylethers of dihydrotetraazabenzoazulenes for use as vasopressin via receptor antagonists - Google Patents
Arylcyclohexylethers of dihydrotetraazabenzoazulenes for use as vasopressin via receptor antagonists Download PDFInfo
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- AU2009319123B2 AU2009319123B2 AU2009319123A AU2009319123A AU2009319123B2 AU 2009319123 B2 AU2009319123 B2 AU 2009319123B2 AU 2009319123 A AU2009319123 A AU 2009319123A AU 2009319123 A AU2009319123 A AU 2009319123A AU 2009319123 B2 AU2009319123 B2 AU 2009319123B2
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- chloro
- trans
- tetraaza
- cyclohexyl
- dihydro
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- KBZOIRJILGZLEJ-LGYYRGKSSA-N argipressin Chemical compound C([C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSC[C@@H](C(N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N1)=O)N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)NCC(N)=O)C1=CC=CC=C1 KBZOIRJILGZLEJ-LGYYRGKSSA-N 0.000 title claims description 33
- 229960003726 vasopressin Drugs 0.000 title claims description 33
- GXBMIBRIOWHPDT-UHFFFAOYSA-N Vasopressin Natural products N1C(=O)C(CC=2C=C(O)C=CC=2)NC(=O)C(N)CSSCC(C(=O)N2C(CCC2)C(=O)NC(CCCN=C(N)N)C(=O)NCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(CCC(N)=O)NC(=O)C1CC1=CC=CC=C1 GXBMIBRIOWHPDT-UHFFFAOYSA-N 0.000 title claims description 32
- 108010004977 Vasopressins Proteins 0.000 title claims description 32
- 102000002852 Vasopressins Human genes 0.000 title claims description 32
- 239000002464 receptor antagonist Substances 0.000 title description 6
- 229940044551 receptor antagonist Drugs 0.000 title description 6
- 150000001875 compounds Chemical class 0.000 claims description 291
- 238000000034 method Methods 0.000 claims description 178
- -1 3-t-butyl-phenyl Chemical group 0.000 claims description 118
- TXGZMKRCQDLREA-UHFFFAOYSA-N tert-butyl benzo[e]azulene-5-carboxylate Chemical compound CC(C)(C)OC(=O)C1=CC2=CC=CC2=C2C=CC=CC2=C1 TXGZMKRCQDLREA-UHFFFAOYSA-N 0.000 claims description 47
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 38
- LGMRJEZNTZJDHP-UHFFFAOYSA-N benzo[e]azulene Chemical compound C1=CC2=CC=CC=C2C2=CC=CC2=C1 LGMRJEZNTZJDHP-UHFFFAOYSA-N 0.000 claims description 29
- AKMVETHPTDOJRB-UHFFFAOYSA-N benzo[e]azulene;hydrochloride Chemical compound Cl.C1=CC2=CC=CC=C2C2=CC=CC2=C1 AKMVETHPTDOJRB-UHFFFAOYSA-N 0.000 claims description 24
- 125000001424 substituent group Chemical group 0.000 claims description 24
- 125000005843 halogen group Chemical group 0.000 claims description 22
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- 125000004093 cyano group Chemical group *C#N 0.000 claims description 19
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- UOUFRTFWWBCVPV-UHFFFAOYSA-N tert-butyl 4-(2,4-dioxo-1H-thieno[3,2-d]pyrimidin-3-yl)piperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(CC1)n1c(=O)[nH]c2ccsc2c1=O UOUFRTFWWBCVPV-UHFFFAOYSA-N 0.000 claims description 14
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- QKIUAMUSENSFQQ-UHFFFAOYSA-N dimethylazanide Chemical compound C[N-]C QKIUAMUSENSFQQ-UHFFFAOYSA-N 0.000 claims description 3
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 claims description 3
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 claims description 3
- 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 claims description 3
- 125000002206 pyridazin-3-yl group Chemical group [H]C1=C([H])C([H])=C(*)N=N1 0.000 claims description 3
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 claims description 3
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- LGNWUMGEJQAWQD-UHFFFAOYSA-N 1h-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine Chemical compound N1=CC2=CC=CC=C2N2CN=NC2=C1 LGNWUMGEJQAWQD-UHFFFAOYSA-N 0.000 claims description 2
- 125000004778 2,2-difluoroethyl group Chemical group [H]C([H])(*)C([H])(F)F 0.000 claims description 2
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- LKRNZLYYWVHIFZ-UHFFFAOYSA-N 4h-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine Chemical compound C1N=CC2=CC=CC=C2N2C=NN=C12 LKRNZLYYWVHIFZ-UHFFFAOYSA-N 0.000 claims description 2
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- 125000001588 azulen-1-yl group Chemical group [H]C1=C([H])C2=C([H])C([H])=C([H])C([H])=C([H])C2=C1* 0.000 claims description 2
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- VWIXROWPCIMRKG-UHFFFAOYSA-N 5,6-dihydro-4h-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine Chemical class C1NCC2=CC=CC=C2N2C=NN=C12 VWIXROWPCIMRKG-UHFFFAOYSA-N 0.000 abstract description 2
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
- A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
- A61K31/5517—1,4-Benzodiazepines, e.g. diazepam or clozapine condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
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- A—HUMAN NECESSITIES
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Abstract
The present invention is concerned with arylcyclohexylethers of dihydro-tetraazabenzoazulene derivatives, i.e. arylcyclohexylethers of 5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene derivatives of formula (I) wherein R
Description
WO 2010/060836 PCT/EP2009/065354 Case 25355 ARYLCYCLOHEXYLETHERS OF DIHYDROTETRAAZABENZOAZULENES FOR USE AS VASOPRESSIN VIA RECEPTOR ANTAGONISTS The present invention is concerned with arylcyclohexylethers of dihydro 5 tetraazabenzoazulene derivatives, i.e. arylcyclohexylethers of 5,6-dihydro-4H-2,3,5,10b-tetraaza benzo[e]azulene derivatives, which act as Vla receptor modulators, and in particular as Vla receptor antagonists, their manufacture, pharmaceutical compositions containing them and their use as medicaments. Technical Field 10 The active compounds of the present invention are useful as therapeutics acting peripherally and centrally in the conditions of dysmenorrhea, male or female sexual dysfunction, hypertension, chronic heart failure, inappropriate secretion of vasopressin, liver cirrhosis, nephrotic syndrome, anxiety, depressive disorders, obsessive compulsive disorder, autistic spectrum disorders, schizophrenia, and aggressive behavior. 15 In particular, the present invention is concerned with arylcyclohexylethers of dihydro tetraazabenzoazulene derivatives of formula I -R R 3 NN N N N N R2 wherein R 1 , R 2 and R 3 are as described in herewithin. Background Art 20 Vasopressin is a 9 amino acid peptide mainly produced by the paraventricular nucleus of the hypothalamus. In the periphery vasopressin acts as a neurohormone and stimulates vasoconstriction, glycogenolysis and antidiuresis. Three vasopressin receptors, all belonging to the class I G-protein coupled receptors, are known. The Via receptor is expressed in the brain, liver, vascular smooth muscle, lung, uterus 25 and testis, the VIb or V3 receptor is expressed in the brain and pituitary gland, the V2 receptor is SMU 24-09-2009 WO 2010/060836 PCT/EP2009/065354 -2 expressed in the kidney where it regulates water reabsorption and mediates the antidiuretic effects of vasopressin (Robben, et al. (2006). Am J Physiol Renal Physiol. 291, F257-70, "Cell biological aspects of the vasopressin type-2 receptor and aquaporin 2 water channel in nephrogenic diabetes insipidus"). Compounds with activity at the V2 receptor may therefore 5 cause side-effects on blood homeostasis. The oxytocin receptor is related to the Vasopressin receptor family and mediates the effects of the neurohormone oxytocin in the brain and the periphery. Oxytocin is believed to have central anxiolytic effects (Neumann (2008). J Neuroendocrinol. 20, 858-65, "Brain oxytocin: a key regulator of emotional and social behaviours in both females and males"). 10 Central oxytocin receptor antagonism might therefore lead to anxiogenic effects, which are regarded as undesired side-effects. In the brain vasopressin acts as a neuromodulator and is elevated in the amygdala during stress (Ebner, et al. (2002). Eur J Neurosci. 15, 384-8., "Forced swimming triggers vasopressin release within the amygdala to modulate stress-coping strategies in rats"). It is known that 15 stressful life events can trigger major depression and anxiety (Kendler, et al. (2003). Arch Gen Psychiatry. 60, 789-96, "Life Event Dimensions of Loss, Humiliation, Entrapment, and Danger in the Prediction of Onsets of Major Depression and Generalized Anxiety") and that both have very high comorbidity, with anxiety often preceding major depression (Regier, et al. (1998). Br J Psychiatry Suppl. 24-8, "Prevalence of anxiety disorders and their comorbidity with mood and 20 addictive disorders"). The Vla receptor is extensively expressed in the brain and particularly in limbic areas like the amygdala, lateral septum and hippocampus which are playing an important role in the regulation of anxiety. Indeed Via knock-out mice show a reduction in anxious behavior in the plus-maze, open field and light-dark box (Bielsky, et al. (2004). Neuropsychopharmacology. 29, 483-93, "Profound impairment in social recognition and 25 reduction in anxiety-like behavior in vasopressin Vla receptor knockout mice"). The downregulation of the Vla receptor using antisense oligonucleotide injection in the septum also causes a reduction in anxious behavior (Landgraf, et al. (1995). Regul Pept. 59, 229-39., "V1 vasopressin receptor antisense oligodeoxynucleotide into septum reduces vasopressin binding, social discrimination abilities, and anxiety-related behavior in rats"). Vasopressin or the Vla 30 receptor are also implicated in other neuropsychological disorders: genetic studies recently linked sequence polymorphism in the promoter of the human VIa receptor to autistic spectrum disorders (Yirmiya, et al. (2006). 11, 488-94, "Association between the arginine vasopressin la receptor (AVPRI a) gene and autism in a family-based study: mediation by socialization skills"), intranasal administration of vasopressin was shown to influence aggression in human males 35 (Thompson, et al. (2004). Psychoneuroendocrinology. 29, 35-48, "The effects of vasopressin on human facial responses related to social communication") and vasopressin levels were found to be elevated in schizophrenic patients (Raskind, et al. (1987). Biol Psychiatry. 22, 453-62, "Antipsychotic drugs and plasma vasopressin in normals and acute schizophrenic patients") and WO 2010/060836 PCT/EP2009/065354 -3 patients with obsessive-compulsive disorder (Altemus, et al. (1992). Arch Gen Psychiatry. 49, 9 20, "Abnormalities in the regulation of vasopressin and corticotropin releasing factor secretion in obsessive-compulsive disorder"). The Via receptor is also mediating the cardiovascular effects of vasopressin in the brain 5 by centrally regulating blood pressure and heart rate in the solitary tract nucleus (Michelini and Morris (1999). Ann N Y Acad Sci. 897, 198-211, "Endogenous vasopressin modulates the cardiovascular responses to exercise"). In the periphery it induces the contraction of vascular smooth muscles and chronic inhibition of the Vla receptor improves hemodynamic parameters in myocardial infarcted rats (Van Kerckhoven, et al. (2002). Eur J Pharmacol. 449, 135-41, 10 "Chronic vasopressin V(1A) but not V(2) receptor antagonism prevents heart failure in chronically infarcted rats"). Hence, Vla antagonists with improved penetration through the blood-brain barrier are expected to be of advantage. A vasopressin Vla receptor antagonist was shown to be effective in reducing dysmenorrhea in the clinic (Brouard, et al. (2000). Bjog. 107, 614-9, "Effect of SR49059, an 15 orally active Via vasopressin receptor antagonist, in the prevention of dysmenorrhoea"). Via receptor antagonism has also been implicated in the treatment of female sexual dysfunction (Aughton, et al. (2008). Br J Pharmacol. doi:10.1038/bjp.2008.253, "Pharmacological profiling of neuropeptides on rabbit vaginal wall and vaginal artery smooth muscle in vitro"). In a recent study Vla receptor antagonists were suggested to have a therapeutic role in both erectile 20 dysfunction and premature ejaculation (Gupta, et al. (2008). Br J Pharmacol. 155, 118-26, "Oxytocin-induced contractions within rat and rabbit ejaculatory tissues are mediated by vasopressin V(1A) receptors and not oxytocin receptors"). Detailed description of the invention It is an object of the present invention to provide compounds which act as Via receptor 25 modulators, and in particular as Vla receptor antagonists. It is a further object of the invention to provide selective inhibitors of the Vla receptor since it is expected that selectivity affords a low potential to cause unwanted off-target related side effects such as discussed above. Such Vla antagonists are useful as therapeutics acting peripherally and centrally in the conditions of dysmenorrhea, male or female sexual dysfunction, hypertension, chronic heart 30 failure, inappropriate secretion of vasopressin, liver cirrhosis, nephrotic syndrome, anxiety, depressive disorders, obsessive compulsive disorder, autistic spectrum disorders, schizophrenia, and aggressive behavior. The preferred indications with regard to the present invention are the treatment of anxiety, depressive disorders, obsessive compulsive disorder, autistic spectrum disorders, schizophrenia, and aggressive behavior. 35 The VIa activity may be detected as described in the experimental section.
WO 2010/060836 PCT/EP2009/065354 -4 The following definitions of the general terms used in the present description apply irrespective of whether the terms in question appear alone or in combination. As used herein, the term "alkyl", alone or in combination with other groups, denotes a saturated, i.e. aliphatic, hydrocarbon group including a straight or branched carbon chain. If not 5 further specified, "aikyl" groups denote groups with I to 12 carbon atoms, like "C1- 1 2 -alkyl". "C1_ 4 -alkyl" denotes alkyl groups with I to 4 carbon atoms and "C 1
_
7 -alkyl" denotes alkyl groups with 1 to 7 carbon atoms. Examples for alkyll" are methyl, ethyl, propyl, isopropyl, n-butyl, iso butyl, sec-butyl, tert-butyl and the like. Preferred are methyl and tert-butyl. The term "alloxy", alone or in combination with other groups, denotes a group -O-R' 10 wherein R' is alkyl as defined above. "C1-1 2 -alkoxy" denotes alkoxy groups with 1 to 12 carbon atoms, "C 1
_
4 -alkoxy" denotes alkoxy groups with 1 to 4 carbon atoms and "C 1
_
7 -alkoxy" denotes atkoxy groups with 1 to 7 carbon atoms. Examples for "alkoxy" are methoxy, ethoxy, propoxy, tert-butoxy and the like. Preferred is methoxy. The term "aromatic" means the presence of an electron sextet in a ring, according to 15 Hiickel's rule. The term "aryl", alone or in combination with other groups, denotes a monovalent cyclic aromatic hydrocarbon moiety consisting of a mono- or bicyclic aromatic ring. Preferred aryl are phenyl or naphthyl. Aryl may be unsubstituted or substituted as described herein. The term "cyano" denotes the group -CN. 20 The term "hydroxy" denotes the group -OH. The term "halo" or "halogen" denotes chloro, iodo, fluoro and bromo. The term "halo-C1_p-alkyl" or "C1 -haloalkyl", alone or in combination with other groups, denotes a C1_-alkyl group as defined above , with 1 to n carbon atoms as defined in the specification, wherein at least one of the hydrogen atoms of the alkyl group is replaced by a 25 halogen atom, preferably fluoro or chloro, most preferably fluoro. Examples of halo-C1 -alkyl include but are not limited to methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, pentyl or n-hexyl substituted by one or more Cl, F, Br or I atom(s), in particular one, two or three fluoro or chloro, as well as those groups specifically illustrated by the examples herein below. Among the preferred halo-C1_-alkyl groups are difluoro- or trifluoro-methyl or -ethyl. 30 The term "hydroxy-C1_n-alkyl" or "Ci_,-hydroxyalkyl", alone or in combination with other groups, denotes a C1_-alkyl group as defined above , with 1 to n carbon atoms, wherein at least one of the hydrogen atoms of the alkyl group is replaced by a hydroxy, i.e. by an OH group. An example for hydroxyalkyl is hydroxyethyl.
WO 2010/060836 PCT/EP2009/065354 -5 The terms "heteroaryl" and "5- or 6-membered heteroaryl", alone or in combination with other groups, refers to a monovalent 5- or 6-membered aromatic monocyclic or 9- or 10 membered aromatic bicyclic ring containing from one to four ring heteroatoms selected from N, 0, or S, the remaining ring atoms being C. Preferably, the monocyclic heteroaryl bears one or 5 two heteroatoms and the bicyclic heteroaryl bears from one to four heteroatoms. 6-Membered heteroaryl are preferred. Examples for heteroaryl moieties include but are not limited to pyridinyl, pyrimidinyl, pyridazinyl or pyrazinyl. Heteroaryl may be unsubstituted or substituted as described herein. The term "heterocycloalkyl", alone or in combination with other groups, as defined 10 herein refers to a monovalent 3 to 7 membered or 4 to 7 membered saturated ring containing one or two heteroatoms selected from N, 0 or S. The term "3- to 7-membered heterocycloalkyl" refers to a monovalent 3 to 7 membered ring containing one or two heteroatoms selected from N, o or S. Examples for heterocycloclakyl moieties are oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, piperidinyl, or piperazinyl. 15 Preferred heterocycloalkyl are oxetanyl and tetrahydrofuranyl. Heterocycloalkyl is optionally substituted as described herein. The term "oxo" when referring to substituents on heterocycloalkyl means that an oxygen atom is attached to the heterocycloalkyl ring. Thereby, the "oxo" may either replace two hydrogen atoms on a carbon atom, or it may simply be attached to sulfur, so that the sulfur exists 20 in oxidized form, i.e. bearing one or two oxygens like a group -S02. When indicating the number of subsituents, the term "one or more" means from one substituent to the highest possible number of substitution, i.e. replacement of one hydrogen up to replacement of all hydrogens by substituents. Thereby, one, two or three substituents are preferred. Even more preferred are one or two substituents or one substituent. 25 The term "pharmaceutically acceptable salt" or "pharmaceutically acceptable acid addition salt" embraces salts with inorganic and organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methane-sulfonic acid, p-toluenesulfonic acid and the like. Preferred is the hydrochloric acid salt. 30 The terms pharmaceuticallyy acceptable carrier" and "pharmaceutically acceptable auxiliary substance" refer to carriers and auxiliary substances such as diluents or excipients that are compatible with the other ingredients of the formulation. The term "pharmaceutical composition" encompasses a product comprising specified ingredients in pre-determined amounts or proportions, as well as any product that results, directly 35 or indirectly, from combining specified ingredients in specified amounts. Preferably it WO 2010/060836 PCT/EP2009/065354 -6 encompasses a product comprising one or more active ingredients, and an optional carrier comprising inert ingredients, as well as any product that results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of 5 one or more of the ingredients. The following table lists abbreviations used within the present document.
(BOC)
2 0 di-tert-butyl dicarbonate
CH
2 Cl 2 dichloromethane
CS
2
CO
3 caesium carbonate Cul copper(I) iodide DEAD diethyl acetylene dicarboxylate DMAP 4-(dimethylamino)-pyridine DMF N,N-dimethylformamide EDTA ethylendiamin-tetraacetate El electron ionization Et 3 N triethylamine HEPES 4-(2-hydroxyethyl)- I -piperazineethanesulfonic acid HPLC high performance liquid chromatography
K
2 C0 3 potassium carbonate Lawesson's reagent 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide MeOH methanol MS mass spectroscopy NaOH sodium hydroxide n-BuOH n-butanol NMR nuclear magnetic resonance PPh 3 triphenylphosphine RNA ribonucleic acid RT room temperature RT-PCR reverse-transcriptase polymerase chain reaction SOCl 2 thionyl chloride T-BuOK potassium tert butanolat THF tetrahydrofurane Tris aluminium-tris(8-hydroxychinolin ZnBr 2 zinc bromide Table 1: abbreviations The invention also provides pharmaceutical compositions, methods of using, and methods of preparing the aforementioned compounds. 10 The compounds of formula I may contain asymmetric carbon atoms. Accordingly, the present invention includes all stereoisomeric forms of the compounds of formula I, including each of the individual stereoisomer and mixtures thereof, i.e. their individual optical isomers and WO 2010/060836 PCT/EP2009/065354 -7 mixtures thereof Additional asymmetric centers may be present depending upon the nature of the various substituents on the molecule. Each such asymmetric centre will independently produce two optical isomers and it is intended that all of the possible optical isomers and diastereomers in mixtures and as pure or partially purified compounds are included within this 5 invention. The present invention is meant to comprehend all such isomeric forms of these compounds. The independent syntheses of these diastereomers or their chromatographic separations may be achieved as known in the art by appropriate modification of the methodology disclosed herein. Their absolute stereochemistry may be determined by the x-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a 10 reagent containing an asymmetric centre of known absolute configuration. If desired, racemic mixtures of the compounds may be separated so that the individual enantiomers are isolated. The separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional 15 crystallization or chromatography. This applies in particular to the arylcyclohexylether-head group (HG) of the compounds of formula I, namely 4 HG wherein at least the carbon atoms 1 and 4 are asymmetric carbon atoms and R, could 20 further comprise asymmetric carbon atoms. It is to be understood that present invention includes all individual stereoisomers of head groups and mixtures thereof. In detail, the present invention is concerned with compounds of formula I OR R 3 N / N N R2 WO 2010/060836 PCT/EP2009/065354 -8 wherein R' is aryl or heteroaryl, unsubstituted or substituted with one or more substituents independently selected from A; R2 is H, 5 C 1 12 -alkyl, unsubstituted or substituted with one or more OH, halo, cyano or C1- 2 -alkoxy,
-(CH
2 )q-Ra, wherein Ra is phenyl or 5- or 6-membered heteroaryl, each unsubstituted or substituted with one or more substituents independently selected from A,
-(CH
2 )rNRR, -C(O)-Cii 2 -alkyl, wherein C- 1 2 -alkyl is unsubstituted or substituted with one or more 10 OH, halo, cyano or CI 1 2 -alkoxy,
-C(O)(CH
2 )qOC(O)-CI-12-akyl,
-C(O)(CH
2 )qNRR, -C(O)O-C1-12-alkyl, wherein alkyl is unsubstituted or substituted with one or more OH, halo, cyano or CI- 2 -alkoxy, 15 -S(O) 2
-CI
1 2 -alkyl,
-S(O)
2 NRR, R and R' are each independently H, Cp 12 -alkyl, or form together with the nitrogen to which they are bound a 3- to 7-membered heterocycloalkyl containing one or two heteroatoms selected from N, 0 or S, which heterocycloalkyl is unsubstituted or substituted by one or more substituents independently selected from B, 20 q is 1, 2, 3 or 4, r is 2, 3 or 4, A is halo, cyano, OH, C 1 7 -alkyl, halo-C 7 -alkyl, C 17 -alkoxy, halo-C 1 7 -alkoxy, or hydroxy-CI- 7 -alkyl, B is oxo, halo, OH, Cp 7 -alkyl or Cp 2 -alkoxy, 25 R 3 is Cl or F, or a pharmaceutically acceptable salt thereof WO 2010/060836 PCT/EP2009/065354 -9 In particular, these head groups HG are 0-R4 0-R4 0- R 0-R HG-1 HG-2 HG-3 HG-4 trans cis It is further understood that all embodiments of the invention as described herein may be combined with each other. 5 In certain embodiments, A is halo, cyano, OH, CI 7 -alkyl, halo-CI1 7 -alkyl, CI 7 -alkoxy, halo-C 1 7 -alkoxy, or hydroxy-CI 7 -alkyl. In certain embodiments, A is halo, cyano, C 1
_
7 -alkyl, halo-C1_ 7 -alkyl, or Ci_ 7 -alkoxy. In certain embodiments, R 1 is aryl or heteroaryl, unsubstituted or substituted with one or more substituents independently selected from A; and A is as defined above. 10 In certain embodiments, R' is a monovalent cyclic aromatic hydrocarbon moiety consisting of a mono- or bicyclic aromatic ring, a monovalent 5- or 6-membered aromatic monocyclic or 9- or 10-membered aromatic bicyclic ring containing from one to four ring heteroatoms selected from N, 0, or S, the remaining ring atoms being C, each unsubstituted or substituted with one or more substituents independently selected from A; and A is as defined 15 above. In certain embodiments, R 1 is phenyl, naphthyl, pyridinyl, pyrimidinyl, pyridazinyl or pyrazinyl, each unsubstituted or substituted with one or more substituents independently selected from A; and A is as defined above. In certain embodiments, R 1 is phenyl, naphthyl, pyridinyl, pyrimidinyl, pyridazinyl or 20 pyrazinyl, each unsubstituted or substituted with one or more substituents independently selected from methyl, t-butyl, Cl, F, trifluoromethyl, methoxy or cyano. In certain embodiments, R 1 is a monovalent cyclic aromatic hydrocarbon moiety consisting of a mono-aromatic ring. In certain embodiments, R 1 is naphthyl, phenyl, pyrazinyl, pyridazinyl, pyridinyl or 25 pyrimidinyl.
WO 2010/060836 PCT/EP2009/065354 - 10 In certain embodiments, R 1 is phenyl or pyridinyl. In certain embodiments, R' is phenyl, 4-fluoro-phenyl, 4-cyanophenyl, 4-trifluoromethyl phenyl, 3-chloro-phenyl, 3-methoxy-phenyl, 3-cyano-phenyl, 3-methyl-phenyl, 3-t-butyl-phenyl, 3-trifluoromethyl-phenyl, 2-fluoro-phenyl, 2-cyano-phenyl, 2-methyl-phenyl, 3,5-di-fluoro 5 phenyl, naphth-2-yl, naphth-1-yl, pyridin-3-yl, 5-chloro-pyridin-3-yl, pyridin-2-yl, 6-chloro pyridin-2-yl, 3-fluoro-pyridin-2-yl, 5-fluoro-pyridin-2-yl, 6-methyl-pyridin-2-yl, 2,6-di-methyl pyrimidin-4-yl, pyrimidin-2-yl, pyrazin-2-yl, pyridin-4-yl or pyridazin-3-yl. In certain embodiments, R' is phenyl, 4-fluoro-phenyl, 4-cyanophenyl, 4-trifluoromethyl phenyl, 3-chloro-phenyl, 3-methoxy-phenyl, 3-cyano-phenyl, 3-methyl-phenyl, 3-t-butyl-phenyl, 10 3-trifluoromethyl-phenyl, 2-fluoro-phenyl, 2-cyano-phenyl, 2-methyl-phenyl, 3,5-di-fluoro phenyl, naphth-2-yl, naphth-1-yl, pyridin-3-yl, 5-chloro-pyridin-3-yl, pyridin-2-yl, 6-chloro pyridin-2-yl, 2,6-di-methyl-pyrimidin-4-yl, pyrimidin-2-yl, pyrazin-2-yl, pyridin-4-yl or pyridazin-3-yl. In certain embodiments, R 2 is as described above. 15 In certain embodiments, R2 is H. Thereby, forming either the free base or a pharmaceutically acceptable acid addition salt with an inorganic or organic acid such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methane-sulfonic acid, p-toluenesulfonic acid and the like. 20 In certain embodiments, R 2 is CI-1 2 -alkyl, unsubstituted or substituted with one or more OH, halo, cyano or CI-1 2 -alkoxy. In certain embodiments, R 2 is C 1
-
1 2 -alkyl, unsubstituted or substituted with one or more OH. In certain embodiments, R 2 is -(CH2)q-Ra, wherein Ra is phenyl or 5- or 6-membered heteroaryl, each unsubstituted or substituted with one or more substituents independently 25 selected from A, and A is as defined above and q is 1, 2, 3 or 4, preferably 1. In certain embodiments, R 2 is -(CH 2 )q-Ra, wherein Ra is phenyl or 5- or 6-membered heteroaryl, each unsubstituted or substituted with one or more substituents independently selected from A, and A is halo, cyano, OH, C1_ 7 -alkyl, halo-C1_ 7 -alkyl, or C1_ 7 -alkoxy; and q is 1, 2, 3 or 4, preferably 1. In certain embodiments, R 2 is -(CH 2 )q-Ra, wherein Ra is phenyl or 5- or 6-membered heteroaryl 30 and q is 1, 2, 3 or 4, preferably 1. In certain embodiments, R 2 is -CH 2 -pyridinyl or benzyl, preferably -CH 2 -pyridin-2-yl. In certain embodiments, R 2 is -C(O)-Ci-1 2 -alkyl, wherein alkyl is unsubstituted or substituted with one or more OH, halo, cyano or C 1
-
1 2 -alkoxy. In certain embodiments, R 2 is C(O)-C 1
-
12 -alkyl.
WO 2010/060836 PCT/EP2009/065354 - 11 In certain embodiments, R 2 is -C(O)(CH 2 )qNRR, wherein q is 1, 2, 3 or 4, preferably 1, and wherein R and R" are each independently H, C1-12-alkyl, or form together with the nitrogen to which they are bound a 3- to 7-membered heterocycloalkyl containing one or two heteroatoms selected from N, 0 or S, which heterocycloalkyl is unsubstituted or substituted by one or more 5 substituents independently selected from B, and B is oxo, halo, OH, C1_ 7 -alkyl or C 1
_
7 -alkoxy. In certain embodiments, R 2 is C(O)(CH 2 )qNRWR, wherein q is 1, 2, 3 or 4, preferably 1, and wherein R and R are each independently H or CI- 12 -alkyl, preferably C1-12-alkyl. In certain embodiments, R2 is -C(O)O-C1- 12 -alkyl, wherein alkyl is unsubstituted or substituted with one or more OH, halo, cyano or C 1
-
12 -alkoxy. In certain embodiments, R2 is 10 -C(O)O-CI-1 2 -alkyl. In certain embodiments, R 2 is -S(O) 2
-C
1
-
12 -alkyl. In certain embodiments, R 2 is -S(O) 2 NRR, wherein R' and R are each independently H, C1-12-alkyl, or form together with the nitrogen to which they are bound a 3- to 7-membered heterocycloalkyl containing one or two heteroatons selected from N, 0 or S, which 15 heterocycloalkyl is unsubstituted or substituted by one or more substituents independently selected from B, and B is oxo, halo, OH, C 1
_
7 -alkyl or C1_ 7 -alkoxy. In certain embodiments, R2 is
-S(O)
2 NRR, wherein R and R are each independently H or C 1
-
12 -alkyl, preferably C1- 12 -alkyl. In certain embodiments, R2 is H, 20 C1- 12 -alkyl, unsubstituted or substituted with one or more OH or F,
-(CH
2 )q-Ra, wherein Ra is phenyl or 5- or 6-membered heteroaryl and q is 1, 2, 3 or 4, preferably 1,
-C(O)-C
1 -12-alkyl,
-C(O)(CH
2 )gNR'R, wherein R and R" are each independently H or C 1
-
12 -alkyl, 25 preferably C 1
-
12 -alkyl, and q is 1, 2, 3 or 4, preferably 1,
-C(O)O-C
1 -1 2 -alkyl,
-S(O)
2 -CI-1 2 -alkyl, or
-S(O)
2 NRR, wherein R and R are each independently H or C1- 12 -alkyl, preferably C1-12-alkyl. 30 In certain embodiments, R 2 is H, CI-1 2 -alkyl, unsubstituted or substituted with one or more OH,
-(CH
2 )q-Ra, wherein Ra is phenyl or 5- or 6-membered heteroaryl and q is 1, 2, 3 or 4, 35 preferably 1, WO 2010/060836 PCT/EP2009/065354 - 12 -C(O)-C-1 2 -atkyl,
-C(O)(CH
2 )gNRR, wherein R and R are each independently H or C 1
-
1 2 -alkyl, preferably CI-1 2 -alkyl, and q is 1, 2, 3 or 4, preferably 1, -C(O)O-C1-12-alkyl, 5 -S(O) 2
-C
1
-
12 -alkyl, or
-S(O)
2 NRR, wherein R and R are each independently H or C 1
-
1 2 -alkyl, preferably C1-1 2 -alkyl. In certain embodiments, R 2 is 2-hydroxy-ethyl, 2-fluoro-ethyl, 2,2-difluoro-ethyl,
-C(O)CH
2 N(Me) 2 , -C(O)methyl, -CH 2 -pyridin-2-yl, -COO-t-butyl, H, i-propyl, methyl, 10 -S(O) 2 methyl or -S(O) 2 N(methyl) 2 . In certain embodiments, R 2 is 2-hydroxy-ethyl, -C(O)CH 2 N(Me) 2 , -C(O)methyl, -CH 2 pyridin-2-yl, -COO-t-butyl, H, 1-propyl, methyl, -S(O) 2 methyl or -S(O) 2 N(methy) 2 . In a certain embodiment, R 3 is Cl or F. In a certain embodiment, R 3 is Cl. In a certain embodiment of the invention, the compound of formula I is provided OR R 3 N N N 15 R wherein R1 is a monovalent cyclic aromatic hydrocarbon moiety consisting of a mono- or bicyclic aromatic ring, a monovalent 5- or 6-membered aromatic monocyclic or 9- or 10 membered aromatic bicyclic ring containing from one to four ring heteroatoms selected 20 from N, 0, or S, the remaining ring atoms being C, each unsubstituted or substituted with one or more substituents independently selected from A;
R
2 is H, C1-1 2 -alkyl, unsubstituted or substituted with one or more OH, -(CH2)q-Ra, wherein Ra is phenyl or 5- or 6-membered heteroaryl and q is 1, 2, 3 or 4, 25 preferably 1, -C(O)-CI-1 2 -alkyl, WO 2010/060836 PCT/EP2009/065354 - 13 -C(O)(CH 2 )qNRR, wherein R' and R" are each independently H or CI-1 2 -alkyl, preferably CI-1 2 -alkyl, and q is 1, 2, 3 or 4, preferably 1, -C(O)O-CI-12-alkyl,
-S(O)
2
-C
1
-
12 -alkyl, or 5 -S(O) 2 NRR, wherein R and R are each independently H or C 1
-
12 -alkyl, preferably
C
1 -1 2 -alkyl,
R
3 is Cl or F, A is halo, cyano, OH, C1_7-alkyl, halo-C 1
_
7 -alkyl, or C1_7-alkoxy, or a pharmaceutically acceptable salt thereof 10 In a certain embodiment of the invention, the compound of formula I is provided as a subset of formula I'
R
3 HG N N N R2 wherein HG is selected from 0-R 0-R .- R 0- R HG-1 HG-2 HG-3 HG-4 15 and R 1 , R 2 and R 3 are as described above, including all combinations thereof Examples for the compound according to the invention are shown in the experimental part and the table below.
WO 2010/060836 PCT/EP2009/065354 -14 Ex Structure Ex Structure Ex Structure N .,N..,, N NN N N NNN N N N N CI C N HHC N\ N H NN 4 I5 6 _0oC N N OH N N N Nl N N NI N ciN /j N\, 0 0 NN DrHCI WO 2010/060836 PCT/EP2009/065354 - 15 Ex Structure Ex Structure Ex Structure - r~ N, 00 13 14 N'15N FIC N -N F F 0 16 ~N 17 /0 Ns N' Cl -N HI F NJ~~ N, N N N N 19 N\ 20 121 N CI NH HOI Ni N NN. N \F 22 N j23 F J24FFN CIN ~ NH HOI N\ NN 25 F F NJ 26 27 C N N\Cl~i NH HC WO 2010/060836 PCT/EP2009/065354 - 16 Ex Structure Ex Structure Ex Structure NN N'N/ 28 3,~ 2O0~N 30 NJ CI N I C)',2K rI NHH 0 _,, 0,," "' N NN N N N N' N NO.> C I NH HCI N ,N, N4 N,0,' N \ N N Y> - aC - 34 N, N' NH-<36
-
NN 0 ciI \I NI N / N
HCI
WO 2010/060836 PCT/EP2009/065354 -17 Ex Structure Ex Structure Ex Structure F F NF N NFN N 43 44 45 N NO CI I ICNH xi HCI N, N, N N 49 50 ec 51 ci C!: N /C 46 O N N4 F Or,/ 48O, N N C CK HCI 54 F F N H ' N N F N 556 HCI N N, Fl N'I N N WO 2010/060836 PCT/EP2009/065354 -18 Ex Structure Ex Structure Ex Structure -N NO,,.N I--(,,.C)~r ,1 "..N '. - ~N, 58 I 59 60 N Nl N C NH HCI CI N (N N N N NIo - r N /a N '-I 61 62 N 63 c N C NH C HCI CI 0,,' Cl ,, NN- N N 64 65 66 CO NH CI NN HCI 00 00 N NN NN N 67 7ci 68 69 N /N 0I -- NH CI HCI 0 N\ ci Nh N N 70 1 71 CI N.. 72 CI 'NCC / I C 0I ): NH CI N
HCI
WO 2010/060836 PCT/EP2009/065354 - 19 Ex Structure Ex Structure Ex Structure CN, N4 N, 0, yNN 73 74 JC N 75 N cl N ClNH Nl HCI N -N N N -NN NN 76 ji -el 78 ', HOI N- 0>., N 0 ,. N -' N 79 80 CIkK~N81 0i NH CT, N - lC N tNJ, 4 o, N NN 0 N 0N CN N, NI N, ,, ,NH 85 86 87 ci N N o WO 2010/060836 PCT/EP2009/065354 -20 Ex Structure Ex Structure Ex Structure N -C " NN NN NN N N N N N / NN , 88 1 89 1 c Cl NH *C-"i NH HCI HCI N N N N 91 92 93 N N N N NNO N N N N NN 94 I 95 N96 I HCI HCI 'Nzz 0 N 0,,1" N 04 O N N N N 9 7 c9 8 9 9 C NN ---N NH F N\ N00 N N Fo 10, F. - 0 C NCI N CI NH WO 2010/060836 PCT/EP2009/065354 -21 Ex Structure Ex Structure Ex Structure N, 0,,, FN F ~N -I 103 104 105 cN N C1 F> C1 NH F N C,'ON. a,,,. N N N' 109 110I X NH Table 2: structures of selected examples Preferred compounds of the invention are shown in the examples. Particularly preferred are trans-8-Chloro-1I-(4-phenoxy-cyclohexyl)-4H,6H-2,3,5,10 b-tetraaza-benzoazulene-5 carboxylic acid tert-butyl ester, 5 trans-8-Chloro-1I-(4-phenoxy-cyclohexyl)-5,6-dihydro-4H-2,3,5,10~b-tetraaza-benzoazulene hydrochloride, trans-8-Chloro-5-methyl-1I-(4-phenoxy-cyclohexyl)-5,6-dihydro-4H-2,3,5,10Ob-tetraaza benzo[e]azulene, trans-1I-[8-Chloro-1I-(4-phenoxy-eyclohexyl)-4H,6H-2,3,5,10~b-tetraaza-benzoazulen-5-yl] 10 ethanone, trans-8-Chloro-5-methanesulfonyl-1 -(4-phenoxy-cyclohexyl)-5,6-dihydro-4H-2,3,5, 10b tetraaza-benzoazulene, trans-2-[8-Chloro-1 -(4-phenoxy-cyclohexyl)-4H,6H-2,3,5,10~b-tetraaza-benzoazulen-5-yl] ethanol1, 15 trans- 8- Chloro -5-isopropyl- 1-(4 -pheno xy-cyc lo hexyl) -5,6 -dihydro -4H-2,3,5,10 b-tetraaza benzoazulene, WO 2010/060836 PCT/EP2009/065354 - 22 trans-8-Chloro- 1-(4-phenoxy-cyclohexyl)-4H,6H-2,3,5, 1 Ob-tetraaza-benzoazulene-5 sulfonic acid dimethylamide, trans-8-Chloro-1-(4-phenoxy-cyclohexyl)-5-pyridin-2-ylmethyl-5,6-dihydro-4H-2,3,5, 10b tetraaza-benzoazulene, 5 trans-1 -[8-Chloro- 1 -(4-phenoxy-cyclohexyl)-4H,6H-2,3,5, 1Ob-tetraaza-benzoazulen-5-yl] 2-dimethylamino-ethanone, trans-8-Fluoro-1-(4-phenoxy-cyclohexyl)-4H,6H-2,3,5, 1Ob-tetraaza-benzo[e]azulene-5 carboxylic acid tert-butyl ester, trans-8-Fluoro-5-methyl-1-(4-phenoxy-cyclohexyl)-5,6-dihydro-4H-2,3,5,10b-tetraaza 10 benzoazulene, cis-8-Chloro- 1 -(4-phenoxy-cyclohexyl)-4H,6H-2,3,5, 1Ob-tetraaza-benzoazulene-5 carboxylic acid tert-butyl ester, cis-8-Chloro-5 -methyl-1-(4-phenoxy-cyclohexyl)-5,6-dihydro-4H-2,3,5, 1 Ob-tetraaza benzoazulene, 15 trans-8-Chloro-1-[4-(4-fluoro-phenoxy)-cyclohexyl]-4H,6H-2,3,5,1 Ob-tetraaza benzoazulene-5-carboxylic acid tert-butyl ester, trans-8-Chloro- 1-[4-(4-fluoro-phenoxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5, 1 Ob-tetraaza benzo[e]azulene hydrochloride, trans-8-Chloro-1-[4-(4-fluoro-phenoxy)-cyclohexyl]-5-methyl-5,6-dihydro-4H-2,3,5,10b 20 tetraaza-benzoazulene, trans-8-Chloro-1-[4-(4-cyano-phenoxy)-cyclohexyl]-4H,6H-2,3,5,10b-tetraaza benzo[e]azulene-5-carboxylic acid tert-butyl ester, trans-4-[4-(8-Chloro-5-methyl-5,6-dihydro-4H-2,3,5,1 Ob-tetraaza-benzo[e]azulen-1-yl) cyclohexyloxy]-benzonitrile, 25 trans-8-Chloro-1-[4-(4-trifluoromethyl-phenoxy)-cyclohexyl]-4H,6H-2,3,5,10b-tetraaza benzo[e]azulene-5-carboxylic acid tert-butyl ester, trans-8-Chloro-1-[4-(3-chloro-phenoxy)-cyclohexyl]-4H,6H-2,3,5,10b-tetraaza benzoazulene-5-carboxylic acid tert-butyl ester, trans-8-Chloro-1-[4-(3-chloro-phenoxy)-cyclohexyl]-5-methyl-5,6-dihydro-4H-2,3,5,10b 30 tetraaza-benzoazulene, trans-8-Chloro- I -[4-(3-methoxy-phenoxy)-cyclohexyl]-4H,6H-2,3,5, 1 Ob-tetraaza benzoazulene-5-carboxylic acid tert-butyl ester, trans-8-Chloro- 1-[4-(3-methoxy-phenoxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5, 1 Ob-tetraaza benzo[e]azulene hydrochloride, 35 trans-8-Chloro-1-[4-(3-methoxy-phenoxy)-cyclohexyl]-5-methyl-5,6-dihydro-4H 2,3,5,1 Ob-tetraaza-benzoazulene, trans-3-[4-(8-Chloro-5-methyl-5,6-dihydro-4H-2,3,5,1Ob-tetraaza-benzoazulen-1-yl) cyclohexyloxy]-benzonitrile, WO 2010/060836 PCT/EP2009/065354 - 23 trans-8-Chloro- 1-(4-m-tolyloxy-cyclohexyl)-4H,6H-2,3,5,1 Ob-tetraaza-benzo [e]azulene-5 carboxylic acid tert-butyl ester, trans-8-Chloro- 1-(4-m-tolyloxy-cyclohexyl)-5,6-dihydro-4H-2,3,5, 1Ob-tetraaza benzo[e]azulene hydrochloride, 5 trans-8-Chloro-5-methyl-1-(4-m-tolyloxy-cyclohexyl)-5,6-dihydro-4H-2,3,5,10b-tetraaza benzo[e]azulene, trans-I-[4-(3-tert-Butyl-phenoxy)-cyclohexyl]-8-chloro-4H,6H-2,3,5, 1 Ob-tetraaza benzo[e]azulene-5-carboxylic acid tert-butyl ester, trans-8-Chloro-1-[4-(2-fluoro-phenoxy)-cyclohexyl]-4H,6H-2,3,5,10b-tetraaza 10 benzo[e]azulene-5-carboxylic acid tert-butyl ester, trans-8-Chloro- 1-[4-(2-fluoro-phenoxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5, 1 Ob-tetraaza benzo[e]azulene hydrochloride, trans-8-Chloro-1-[4-(2-fluoro-phenoxy)-cyclohexyl]-5-methyl-5,6-dihydro-4H-2,3,5,10b tetraaza-benzo[e]azulene, 15 trans-8-Chloro-1-[4-(2-cyano-phenoxy)-cyclohexyl]-4H,6H-2,3,5,10b-tetraaza benzoazulene-5-carboxylic acid tert-butyl ester, trans-2-[4-(8-Chloro-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulen-1-yl) cyclohexyloxy]-benzonitrile hydrochloride, trans-2-[4-(8-Chloro-5-methyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulen-1-yl) 20 cyclohexyloxy]-benzonitrile, trans-8-Chloro- 1-(4-o-tolyloxy-cyclohexyl)-4H,6H-2,3,5, 1 Ob-tetraaza-benzoazulene-5 carboxylic acid tert-butyl ester, trans-8-Chloro-5-methyl- 1 -(4-o-tolyloxy-cyclohexyl)-5,6-dihydro-4H-2,3,5,1 Ob-tetraaza benzoazulene, 25 trans-8-Chloro- 1-[4-(3,5-difluoro-phenoxy)-cyclohexyl]-4H,6H-2,3,5, 1 Ob-tetraaza benzoazulene-5-carboxylic acid tert-butyl ester, trans-8-Chloro- 1-[4-(3,5-difluoro-phenoxy)-cyclohexyl]-5-methyl-5,6-dihydro-4H 2,3,5,1 Ob-tetraaza-benzoazulene, trans-8-Chloro- 1-[4-(naphthalen-2-yloxy)-cyclohexyl]-4H,6H-2,3,5, 1 Ob-tetraaza 30 benzoazulene-5-carboxylic acid tert-butyl ester, trans-8-Chloro-5-methyl- 1-[4-(naphthalen-2-yloxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5,1 Ob tetraaza-benzoazulene, trans-8-Chloro- 1-[4-(pyridin-3-yloxy)-cyclohexyl] -4H,6H-2,3,5, I Ob-tetraaza benzoazulene-5-carboxylic acid tert-butyl ester, 35 trans-8-Chloro-5-methyl- 1-[4-(pyridin-3-yloxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5, 1 Ob tetraaza-benzoazulene, trans-8-Chloro- 1-[4-(5-chloro-pyridin-3-yloxy)-cyclohexyl]-4H,6H-2,3,5,1 Ob-tetraaza benzoazulene-5-carboxylic acid tert-butyl ester, WO 2010/060836 PCT/EP2009/065354 - 24 trans-8-Chloro- 1-[4-(5-chloro-pyridin-3-yloxy)-cyclohexyl]-5-methyl-5,6-dihydro-4H 2,3,5,1 Ob-tetraaza-benzoazulene, trans-8-Chloro- 1-[4-(pyridin-2-yloxy)-cyclohexyl] -4H,6H-2,3,5, 1 Ob-tetraaza benzoazulene-5-carboxylic acid tert-butyl ester, 5 trans-8-Chloro-1-[4-(pyridin-2-yloxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b-tetraaza benzoazulene hydrochloride, trans-8-Chloro-5-methyl-1-[4-(pyridin-2-yloxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b tetraaza-benzoazulene, trans-8-Chloro-1-[4-(6-chloro-pyridin-2-yloxy)-cyclohexyl]-4H,6H-2,3,5,10b-tetraaza 10 benzo[e]azulene-5-carboxylic acid tert-butyl ester, trans-8-Chloro-1-[4-(6-chloro-pyridin-2-yloxy)-cyclohexyl]-5-methyl-5,6-dihydro-4H 2,3,5,1 Ob-tetraaza-benzo[e]azulene, trans-8-Chloro-1-[4-(5-chloro-pyridin-2-yloxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b tetraaza-benzo[e]azulene hydrochloride, 15 trans-8-Chloro-1-[4-(5-chloro-pyridin-2-yloxy)-cyclohexyl]-5-methyl-5,6-dihydro-4H 2,3,5,1 Ob-tetraaza-benzo[e]azulene, trans-8-Chloro-1-[4-(pyrimidin-2-yloxy)-cyclohexyl]-4H,6H-2,3,5,1Ob-tetraaza benzo[e]azulene-5-carboxylic acid tert-butyl ester, cis-8-Chloro- 1- [4-(pyrimidin-2-yloxy)-cyclohexyl] -4H,6H-2,3,5, 1 Ob-tetraaza 20 benzo[e]azulene-5-carboxylic acid tert-butyl ester, trans-8-Chloro-5-methyl-1-[4-(pyrimidin-2-yloxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b tetraaza-benzo[e]azulene, trans-8-Chloro-1-[4-(pyrazin-2-yloxy)-cyclohexyl]-4H,6H-2,3,5,1 Ob-tetraaza benzo[e]azulene-5-carboxylic acid tert-butyl ester, 25 trans- 8-Chloro-5-methyl-1-[4-(pyrazin-2-yloxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b tetraaza-benzo[e]azulene, trans-8-Chloro-1-[4-(pyrimidin-4-yloxy)-cyclohexyl]-4H,6H-2,3,5,10b-tetraaza benzo[e]azulene-5-carboxylic acid tert-butyl ester, trans-8-Chloro-5-methyl-1-[4-(pyrimidin-4-yloxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b 30 tetraaza-benzo[e]azulene, trans-8-Chloro-1-[4-(pyridazin-3-yloxy)-cyclohexyl]-4H,6H-2,3,5,IOb-tetraaza benzo[e]azulene-5-carboxylic acid tert-butyl ester, cis-8-Chloro- 1- [4-(pyridazin-3 -yloxy)-cyclohexyl] -4H,6H-2,3,5, I Ob-tetraaza benzo[e]azulene-5-carboxylic acid tert-butyl ester, 35 trans-8-Chloro-5-methyl-1-[4-(pyridazin-3-yloxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b tetraaza-benzo[e]azulene, cis-8-Chloro- 1- [4-(pyridin-2-yloxy)-cyclohexyl] -4H,6H-2,3,5,1 Ob-tetraaza benzo[e]azulene-5-carboxylic acid tert-butyl ester , WO 2010/060836 PCT/EP2009/065354 - 25 cis-8-Chloro- 1-[4-(pyridin-2-yloxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5, 1 Ob-tetraaza benzo[e]azulene , cis-8-Chloro-5 -methyl-i -[4-(pyridin-2-yloxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5, I Ob tetraaza-benzo[e]azulene , 5 trans-8-Chloro-1-[4-(3-fluoro-pyridin-2-yloxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b tetraaza-benzo[e]azulcne, trans-8-Chloro-1-[4-(3-fluoro-pyridin-2-yloxy)-cyclohexyl]-5-methyl-5,6-dihydro-4H 2,3,5,10b-tetraaza-benzo[e]azulene , trans-8-Chloro-1-[4-(5-fluoro-pyridin-2-yloxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b 10 tetraaza-benzo[e]azulene , trans-8-Chloro-1-[4-(5-fluoro-pyridin-2-yloxy)-cyclohexyl]-5-methyl-5,6-dihydro-4H 2,3,5,1 Ob-tetraaza-benzo[e]azulene , trans-8-Chloro-1-[4-(6-methyl-pyridin-2-yloxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b tetraaza-benzo[e]azulene , 15 trans-8-Chloro-5-(2,2-difluoro-ethyl)-1-[4-(6-methyl-pyridin-2-yloxy)-cyclohexyl]-5,6 dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene , trans-8-Chloro-5-(2-fluoro-ethyl)- 1 -[4-(5 -fluoro-pyridin-2-yloxy)-cyclohexyl] -5,6-dihydro 4H-2,3,5,10b-tetraaza-benzo[e]azulene , trans-8-Chloro-5-ethyl- 1- [4-(3-fluoro-pyridin-2-yloxy)-cyclohexyl] -5,6-dihydro-4H 20 2,3,5,1 Ob-tetraaza-benzo[e]azulene , trans-8-Chloro-5-ethyl- 1- [4-(5-fluoro-pyridin-2-yloxy)-cyclohexyl] -5,6-dihydro-4H 2,3,5,10b-tetraaza-benzo[e]azulene , trans-8-Chloro-5-ethyl- 1- [4-(6-methyl-pyridin-2-yloxy)-cyclohexyl] -5,6-dihydro-4H 2,3,5,10b-tetraaza-benzo[e]azulene , or 25 trans-8-Chloro-5-methyl-1-[4-(6-methyl-pyridin-2-yloxy)-cyclohexyl]-5,6-dihydro-4H 2,3,5,1 Ob-tetraaza-benzo [e]azulene. More preferred compounds are trans-8-Chloro- I -(4-phenoxy-cyclohexyl)-4H,6H-2,3,5, 1 Ob-tetraaza-benzoazulene-5 carboxylic acid tert-butyl ester, 30 trans-8-Chloro-1-(4-phenoxy-cyclohexyl)-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene hydrochloride, trans-8-Chloro-5-methyl- 1 -(4-phenoxy-cyclohexyl)-5,6-dihydro-4H-2,3,5, 1 Ob-tetraaza benzo[e]azulene, trans-I -[8-Chloro- 1 -(4-phenoxy-cyclohexyl)-4H,6H-2,3,5, 1 Ob-tetraaza-benzoazulen-5-yl] 35 ethanone, trans-8-Chloro-5-methanesulfonyl- 1 -(4-phenoxy-cyclohexyl)-5,6-dihydro-4H-2,3,5, 1 Ob tetraaza-benzoazulene, WO 2010/060836 PCT/EP2009/065354 - 26 trans-2-[8-Chloro- 1 -(4-phenoxy-cyclohexyl)-4H,6H-2,3,5,1 Ob-tetraaza-benzoazulen-5-yl] ethanol, trans-8-Chloro-5-isopropyl- 1 -(4-phenoxy-cyclohexyl)-5,6-dihydro-4H-2,3,5, I Ob-tetraaza benzoazulene, 5 trans-8-Chloro- 1 -(4-phenoxy-cyclohexyl)-4H,6H-2,3,5, 1 Ob-tetraaza-benzoazulene-5 sulfonic acid dimethylamide, trans-8-Chloro- 1 -(4-phenoxy-cyclohexyl)-5-pyridin-2-ylmethyl-5,6-dihydro-4H-2,3,5, 1 Ob tetraaza-benzoazulene, trans-I -[8-Chloro- 1 -(4-phenoxy-cyclohexyl)-4H,6H-2,3,5, 1 Ob-tetraaza-benzoazulen-5-yl] 10 2-dimethylamino-ethanone, trans-8-Fluoro- 1-(4-phenoxy-cyclohexyl)-4H,6H-2,3,5, 1 Ob-tetraaza-benzo [e]azulene-5 carboxylic acid tert-butyl ester, trans-8-Fluoro-5-methyl- 1 -(4-phenoxy-cyclohexyl)-5,6-dihydro-4H-2,3,5, 1 Ob-tetraaza benzoazulene, 15 cis-8-Chloro- 1 -(4-phenoxy-cyclohexyl)-4H,6H-2,3,5, 1 Ob-tetraaza-benzoazulene-5 carboxylic acid tert-butyl ester, cis-8-Chloro-5 -methyl-i -(4-phenoxy-cyclohexyl)-5,6-dihydro-4H-2,3,5, 1 Ob-tetraaza benzoazulene, trans-8-Chloro- 1 -[4-(4-fluoro-phenoxy)-cyclohexyl]-4H,6H-2,3,5, 1 Ob-tetraaza 20 benzoazulene-5-carboxylic acid tert-butyl ester, trans-8-Chloro- 1 -[4-(4-fluoro-phenoxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5, 1 Ob-tetraaza benzo[e]azulene hydrochloride, trans-8-Chloro-1-[4-(4-fluoro-phenoxy)-cyclohexyl]-5-methyl-5,6-dihydro-4H-2,3,5,10b tetraaza-benzoazulene, 25 trans-8-Chloro-1-[4-(4-cyano-phenoxy)-cyclohexyl]-4H,6H-2,3,5,10b-tetraaza benzo[e]azulene-5-carboxylic acid tert-butyl ester, trans-4-[4-(8-Chloro-5-methyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulen-1-yl) cyclohexyloxy]-benzonitrile, trans-8-Chloro-1-[4-(4-trifluoromethyl-phenoxy)-cyclohexyl]-4H,6H-2,3,5,10b-tetraaza 30 benzo[e]azulene-5-carboxylic acid tert-butyl ester, trans-8-Chloro- I -[4-(3-chloro-phenoxy)-cyclohexyl]-4H,6H-2,3,5,1 Ob-tetraaza benzoazulene-5-carboxylic acid tert-butyl ester, trans-8-Chloro-1-[4-(3-chloro-phenoxy)-cyclohexyl]-5-methyl-5,6-dihydro-4H-2,3,5,10b tetraaza-benzoazulene, 35 trans-8-Chloro-1-[4-(3-methoxy-phenoxy)-cyclohexyl]-4H,6H-2,3,5,10b-tetraaza benzoazulene-5-carboxylic acid tert-butyl ester, trans-8-Chloro-1-[4-(3-methoxy-phenoxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b-tetraaza benzo[e]azulene hydrochloride, WO 2010/060836 PCT/EP2009/065354 - 27 trans-8-Chloro-I -[4-(3-methoxy-phenoxy)-cyclohexyl]-5-methyl-5,6-dihydro-4H 2,3,5,1 Ob-tetraaza-benzoazulene, trans-3-[4-(8-Chloro-5-methyl-5,6-dihydro-4H-2,3,5, 1Ob-tetraaza-benzoazulen-1-yl) cyclohexyloxy]-benzonitrile, 5 trans-8-Chloro-1-(4-m-tolyloxy-cyclohexyl)-4H,6H-2,3,5,10b-tetraaza-benzo[e]azulene-5 carboxylic acid tert-butyl ester, trans-8-Chloro-1-(4-m-tolyloxy-cyclohexyl)-5,6-dihydro-4H-2,3,5,10b-tetraaza benzo[e]azulene hydrochloride, trans-8-Chloro-5-methyl- 1 -(4-m-tolyloxy-cyclohexyl)-5,6-dihydro-4H-2,3,5, 1 Ob-tetraaza 10 benzo[e]azulene, trans-I -[4-(3-tert-Butyl-phenoxy)-cyclohexyl]-8-chloro-4H,6H-2,3,5, 1 Ob-tetraaza benzo[e]azulene-5-carboxylic acid tert-butyl ester, trans-8-Chloro- 1 -[4-(2-fluoro-phenoxy)-cyclohexyl]-4H,6H-2,3,5, 1 Ob-tetraaza benzo[e]azulene-5-carboxylic acid tert-butyl ester, 15 trans-8-Chloro-1-[4-(2-fluoro-phenoxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b-tetraaza benzo[e]azulene hydrochloride, trans-8-Chloro-1-[4-(2-fluoro-phenoxy)-cyclohexyl]-5-methyl-5,6-dihydro-4H-2,3,5,10b tetraaza-benzo[e]azulene, trans-8-Chloro-1-[4-(2-cyano-phenoxy)-cyclohexyl]-4H,6H-2,3,5,10b-tetraaza 20 benzoazulene-5-carboxylic acid tert-butyl ester, trans-2-[4-(8-Chloro-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulen-1-yl) cyclohexyloxy]-benzonitrile hydrochloride, trans-2-[4-(8-Chloro-5-methyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulen-1-yl) cyclohexyloxy]-benzonitrile, 25 trans-8-Chloro-1-(4-o-tolyloxy-cyclohexyl)-4H,6H-2,3,5,10b-tetraaza-benzoazulene-5 carboxylic acid tert-butyl ester, trans-8-Chloro-5-methyl-1-(4-o-tolyloxy-cyclohexyl)-5,6-dihydro-4H-2,3,5,10b-tetraaza benzoazulene, trans-8-Chloro-1-[4-(3,5-difluoro-phenoxy)-cyclohexyl]-4H,6H-2,3,5,10b-tetraaza 30 benzoazulene-5-carboxylic acid tert-butyl ester, trans-8-Chloro- I -[4-(3,5 -difluoro-phenoxy)-cyclohexyl] -5-methyl -5,6-dihydro-4H 2,3,5,1 Ob-tetraaza-benzoazulene, trans-8-Chloro-1-[4-(naphthalen-2-yloxy)-cyclohexyl]-4H,6H-2,3,5, I Ob-tetraaza benzoazulene-5-carboxylic acid tert-butyl ester, 35 trans-8-Chloro-5-methyl- 1 -[4-(naphthalen-2-yloxy)-cyclohexyl]-5,6-dihydro-4H 2,3,5,1 Ob-tetraaza-benzoazulene, trans-8-Chloro- 1 -[4-(pyridin-3-yloxy)-cyclohexyl]-4H,6H-2,3,5, 1 Ob-tetraaza benzoazulene-5-carboxylic acid tert-butyl ester, WO 2010/060836 PCT/EP2009/065354 - 28 trans-8-Chloro-5-methyl- I -[4-(pyridin-3-yloxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5,1 Ob tetraaza-benzoazulene, trans-8-Chloro-1-[4-(5-chloro-pyridin-3-yloxy)-cyclohexyl]-4H,6H-2,3,5, 1Ob-tetraaza benzoazulene-5-carboxylic acid tert-butyl ester, 5 trans-8-Chloro-1-[4-(5-chloro-pyridin-3-yloxy)-cyclohexyl]-5-methyl-5,6-dihydro-4H 2,3,5,1 Ob-tetraaza-benzoazulene, trans-8-Chloro-1-[4-(pyridin-2-yloxy)-cyclohexyl]-4H,6H-2,3,5, 1Ob-tetraaza benzoazulene-5-carboxylic acid tert-butyl ester, trans-8-Chloro-1-[4-(pyridin-2-yloxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5, 1 Ob-tetraaza 10 benzoazulene hydrochloride, trans-8-Chloro-5-methyl-1-[4-(pyridin-2-yloxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b tetraaza-benzoazulene, trans-8-Chloro-1-[4-(6-chloro-pyridin-2-yloxy)-cyclohexyl]-4H,6H-2,3,5,10b-tetraaza benzo[e]azulene-5-carboxylic acid tert-butyl ester, 15 trans-8-Chloro-1-[4-(6-chloro-pyridin-2-yloxy)-cyclohexyl]-5-methyl-5,6-dihydro-4H 2,3,5,1 Ob-tetraaza-benzo[e]azulene, trans-8-Chloro-1-[4-(5-chloro-pyridin-2-yloxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b tetraaza-benzo[e]azulene hydrochloride, trans-8-Chloro-1-[4-(5-chloro-pyridin-2-yloxy)-cyclohexyl]-5-methyl-5,6-dihydro-4H 20 2,3,5,1 Ob-tetraaza-benzo[e]azulene, trans-8-Chloro-1-[4-(pyrimidin-2-yloxy)-cyclohexyl]-4H,6H-2,3,5,10b-tetraaza benzo[e]azulene-5-carboxylic acid tert-butyl ester, cis-8-Chloro-1-[4-(pyrimidin-2-yloxy)-cyclohexyl]-4H,6H-2,3,5,10b-tetraaza benzo[e]azulene-5-carboxylic acid tert-butyl ester, 25 trans-8-Chloro-5-methyl- I -[4-(pyrimidin-2-yloxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5, 1 Ob tetraaza-benzo [e]azulene, trans-8-Chloro- 1 -[4-(pyrazin-2-yloxy)-cyclohexyl] -4H,6H-2,3,5, 1 Ob-tetraaza benzo[e]azulene-5-carboxylic acid tert-butyl ester, trans- 8-Chloro-5-methyl-1-[4-(pyrazin-2-yloxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b 30 tetraaza-benzo[e]azulene, trans-8-Chloro- I -[4-(pyrimidin-4-yloxy)-cyclohexyl]-4H,6H-2,3,5,1 Ob-tetraaza benzo[e]azulene-5-carboxylic acid tert-butyl ester, trans-8-Chloro-5-methyl-I-[4-(pyrimidin-4-yloxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b tetraaza-benzo[e]azulene, 35 trans-8-Chloro-1-[4-(pyridazin-3-yloxy)-cyclohexyl]-4H,6H-2,3,5,10b-tetraaza benzo[e]azulene-5-carboxylic acid tert-butyl ester, cis-8-Chloro-1-[4-(pyridazin-3 -yloxy)-cyclohexyl]-4H,6H-2,3,5,10b-tetraaza benzo[e]azulene-5-carboxylic acid tert-butyl ester, or WO 2010/060836 PCT/EP2009/065354 - 29 trans-8-Chloro-5-methyl- 1-[4-(pyridazin-3-yloxy)-cyclohexyl]-5,6-dihydro-4H 2,3,5,1 Ob-tetraaza-benzo [e]azulene. Particularly preferred are trans-8-Chloro-5 -methyl-i -(4-phenoxy-cyc lohexyl)-5,6 dihydro-4H-2,3,5,1Ob-tetraaza-benzo[e]azulene and trans-8-Chloro-5-methyl-1 -[4-(pyridin-2 5 yloxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene.. Most preferred is trans-8-Chloro-5-methyl-1-[4-(pyridin-2-yloxy)-cyclohexyl]-5,6 dihydro-4H-2,3,5,10b-tetraaza-benzoazulene. A certain embodiment of the invention is a compound as described in any of the embodiments obtainable by a process according as described herewithin. 10 A certain embodiment of the invention is a compound as described in any of the embodiments, whenever obtained by a process according as described herewithin. A certain embodiment of the invention is a compound as described in any of the embodiments for the use as therapeutically active substance. A certain embodiment of the invention is a compound as described in any of the 15 embodiments for a use in the prevention or treatment of dysmenorrhea, male or female sexual dysfunction, hypertension, chronic heart failure, inappropriate secretion of vasopressin, liver cirrhosis, nephrotic syndrome, anxiety, depressive disorders, obsessive compulsive disorder, autistic spectrum disorders, schizophrenia, and aggressive behavior. A certain embodiment of the invention is a pharmaceutical composition comprising a 20 compound as described in any of the embodiments. A certain embodiment of the invention is a pharmaceutical composition comprising a compound as described in any of the embodiments, wherein it is useful for the prevention or treatment of dysmenorrhea, male or female sexual dysfunction, hypertension, chronic heart failure, inappropriate secretion of vasopressin, liver cirrhosis, nephrotic syndrome, anxiety, 25 depressive disorders, obsessive compulsive disorder, autistic spectrum disorders, schizophrenia, and aggressive behavior. A certain embodiment of the invention is the use of a compound as described in any of the embodiments for the preparation of a medicament. A certain embodiment of the invention is the use of a compound as described in any of 30 the embodiments for the preparation of a medicament, wherein the medicament is useful for the prevention or treatment of dysmenorrhea, male or female sexual dysfunction, hypertension, chronic heart failure, inappropriate secretion of vasopressin, liver cirrhosis, nephrotic syndrome, WO 2010/060836 PCT/EP2009/065354 - 30 anxiety, depressive disorders, obsessive compulsive disorder, autistic spectrum disorders, schizophrenia, and aggressive behavior. A certain embodiment of the invention is the use of a compound as described in any of the embodiments for the prevention or treatment of dysmenorrhea, male or female sexual 5 dysfunction, hypertension, chronic heart failure, inappropriate secretion of vasopressin, liver cirrhosis, nephrotic syndrome, anxiety, depressive disorders, obsessive compulsive disorder, autistic spectrum disorders, schizophrenia, and aggressive behavior. A certain embodiment of the invention is a method for the therapeutic and/or prophylactic treatment of dysmenorrhea, male or female sexual dysfunction, hypertension, 10 chronic heart failure, inappropriate secretion of vasopressin, liver cirrhosis, nephrotic syndrome, anxiety, depressive disorders, obsessive compulsive disorder, autistic spectrum disorders, schizophrenia, and aggressive behavior, which method comprises administering a compound as defined in any if the embodiments to a human being or animal. In a certain embodiment, the compounds of formula (I) of the invention can be 15 manufactured according to a process comprising the step of reacting a compound of formula (11) R H
N,
NH
2 0 11 with a compound of formula (III) H S N N to obtain a compound of formula (I) wherein R 1 , R2 and R 3 are as defined hereinabove for 20 formula (I). The processes are described in more detail with the following general schemes and procedures A to G.
WO 2010/060836 PCT/EP2009/065354 -31 H S R NH2 R R n-butanol N N, + I ~N'
NH
2 R 3 N reflux R 2 II III Scheme 1: General Scheme A Compounds of formula (1) can be prepared by thermal condensation of a hydrazide derivative of formula (II) and a thiolactam derivative of formula (III). The synthesis of 5 compounds of formula (II) is outlined in general schemes D-G hereinafter. Compounds of formula (111) can be prepared following the general scheme C as described hereinafter. General scheme A is hereinafter further illustrated with general procedure V. acid N R N N 0 I-a I-b R 1) R'R"C(=O),solvent 2) reducing agent N or N
R
2 -LG, base, solvent R 3 N R2 Scheme 2: General Scheme B 10 Compounds of formula (I) with R 2 different from H can be prepared from compounds of formula (I-b) (compounds of formula (I) wherein R 2 is H) according to methods known in the art, e.g. by treating a compound of formula (I-b) with an inorganic base such as a carbonate salt or an organic base such as a tertiary amine and an electrophilic reactant R2-LG (wherein LG is a leaving group, e.g. halogen or sulfonyl) which is either commercially available or easily 15 prepared according to methods and starting materials well known in the art. Alternatively, WO 2010/060836 PCT/EP2009/065354 - 32 compounds of formula (I) can be obtained via reductive alkylation by consecutively treating a compound of formula (I-b) with a ketone or aldehyde and a suitable reducing agent, e.g. a borohydride derivative such as sodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride. Compounds of formula (I-b) can be obtained by cleavage of the 5 substituent R 2 of compound of formula I using methods known in the art. Compounds of formula (1-b) are conveniently obtained as the salt or the free base after basic aqueous work-up by treatment of compounds of formula (I-a) (compounds of formula (I) in which R 2 is tert butoxycarbonyl) with an acid in a suitable solvent, e.g. methanesulfonic acid in dichloromethane or tetrahydrofuran or hydrochloric acid in methanol. General scheme C is hereinafter further 10 illustrated with general procedures VI and VII. glycine ethyl ester
NO
2
SOCI
2 , NO 2 hydrochloride, NO2 Et 3 N Et 3 N R1 )0 RR 0 OH CH2Cl21 CI ethanol, HN OH CHC 2 ,C reflux a b c
(BOC)
2 0 (2 eq.),
NO
2 H 2 , ZnBr 2 , NH2 DMAP (cat.) Pd/C
CH
2 Cl 2 0 R EtOAc, 0 0 Cto RT O N 0-- RT OYN O d e H 0 Lawesson's H S t-BuOK N reagent N THF 3 N THF 3 N 0 *C to RT R N reflux R N 0 O f 1 1 1 Scheme 3: General Scheme C Thiolactam derivatives of formula (III-1) (compounds of formula (III) in which R 2 is tert butoxycarbonyl) can be obtained as follows: Transformation of a 2-nitrobenzyl alcohol of 15 formula (a) to a benylic chloride of formula (b) can be effected by a chlorinating reagent such as thionyl chloride in the presence of an organic tertiary amine base. Alkylation of a compound of formula (b) with glycine ethyl ester hydrochloride in the presence of an organic tertiary amine base and N-protection of the resulting compound of formula (c) using di-tert-butyl dicarbonate and a catalytic amount of 4-N,N-dimethylaminopyridine gives compounds of formula (d). The 20 nitro group can be reduced selectively by hydrogenation over palladium on charcoal, which has WO 2010/060836 PCT/EP2009/065354 - 33 been pretreated with a zinc halide such as zinc bromide, to give aniline intermediates of formula (e). Cyclization to lactams of formula (f) is achieved by treatment of compounds of formula (e) with a suitable base, e.g. potassium tert-butoxide, in tetrahydrofuran. A thiolactam derivative of formula (111-1) is obtained by treatment of a compound of formula (f) with Lawesson's reagent 5 (2,4-bis-(4-methoxyphenyl)- 1,3,2,4-dithiadiphosphetane-2,4-disulfide) or phosphorous pentasulfide at elevated temperature. PPh 3 , HO DEAD, R0 O + R 1 -OH THF 0 o' -Q RT O R 0R IV-1 V VI-1 HO PPh3 DEAD' R 0 + R 1 -OH THE 0
O
0 C - RT R OR IV-2 V VI-2 R Me, Et Scheme 4: General Scheme D Etherification of a 4-hydroxy-cyclohexanecarboxylic acid ester of formula (IV) with a 10 phenol derivative of formula (V) under Mitsunobu conditions leads to a 4-aryloxy cyclohexanecarboxylic acid ester of formula (VI) under inversion of configuration. Thus trans-4 aryloxy-cyclohexanecarboxylic acid esters of formula (VI-1) are obtained from a cis-4-hydroxy cyclohexanecarboxylic acid ester of formula (IV-1), while cis-4-aryloxy-cyclohexanecarboxylic acid esters of formula (VI-2) are obtained from a trans-4-hydroxy-cyclohexanecarboxylic acid 15 ester of formula (IV-2). HO sodium methanesulfinate, K 2 CO 3, DMF, 120'C R1-O 0 + R 1 -CI or O' R Cul, 1,10-phenanthroline, Cs 2
CO
3 , 0, toluene, reflux R IV VII VI-a R = Me, Et R1 = Heteroaryl Scheme 5: General Scheme E WO 2010/060836 PCT/EP2009/065354 - 34 Compounds of formula (VI-a) (compounds of formula (VI) in which R 1 is heteroaryl) can be prepared from a 4-hydroxy-cyclohexanecarboxylic acid ester of formula (IV) and a heteroaryl chloride of formula (VII) in the presence of a catalytic or stoichiometric amount of sodium methanesulfinate and a base such as potassium carbonate in DMF at 120 'C or in the presence of 5 a catalyst system formed from cuprous iodide and 1,10-phenanthroline and a base such as cesium carbonate in toluene at reflux. CI A O H Pd/C, EtsN A O E 4yO O __E__3_O G ethyl acetate, RT G OsO R R VI-b VI R = Me, Et Scheme 6: General Scheme F Compounds of formula (VI-b) (compounds of formula (VI) in which R 1 is substituted 10 with Cl) can be dechlorinated under hydrogenolytic conditions in the presence of palladium on charcoal and triethylamine in ethyl acetate at room temperature. R "O hydrazine R hydrate neat or n-BuOH, HN, O R 120 C
NH
2 R Me, Et VI II 1) ethyl chloroformate, 2 M aq NaOH EtaN, THF, 00 1,4-dioxane, RT 2) hydrazine hydrate, MeOH, RT R0 OH VIII Scheme 7: General Scheme G A 4-aryloxy-cyclohexanecarboxylic acid ester of formula (VI) can be converted to a 15 hydrazide derivative of formula (II) by heating with hydrazine hydrate. Alternatively, an ester derivative of formula (VI) can be hydrolyzed to a carboxylic acid derivative of formula (VIII) using a biphasic mixture of aqueous sodium or potassium hydroxide solution and an etheral WO 2010/060836 PCT/EP2009/065354 - 35 solvent such as dioxan. A hydrazide derivative of formula (II) can be obtained by activating an acid intermediate of formula (VIII), e.g. with ethyl chloroformate, thionyl chloride, oxalylchloride or a peptide coupling reagent, and subsequent coupling with hydrazine. The corresponding pharmaceutically acceptable salts with acids can be obtained by 5 standard methods known to the person skilled in the art, e.g. by dissolving the compound of formula I in a suitable solvent such as e.g. dioxan or THF and adding an appropriate amount of the corresponding acid. The products can usually be isolated by filtration or by chromatography. The conversion of a compound of formula I into a pharmaceutically acceptable salt with a base can be carried out by treatment of such a compound with such a base. One possible method to 10 form such a salt is e.g. by addition of 1/n equivalents of a basic salt such as e.g. M(OH)", wherein M = metal or ammonium cation and n = number of hydroxide anions, to a solution of the compound in a suitable solvent (e.g. ethanol, ethanol-water mixture, tetrahydrofuran-water mixture) and to remove the solvent by evaporation or lyophilisation. Insofar as their preparation is not described in the examples, the compounds of formula I as 15 well as all intermediate products can be prepared according to analogous methods or according to the methods set forth herewithin. Starting materials are commercially available, known in the art or can be prepared by methods known in the art or in analogy thereto. It will be appreciated that the compounds of general formula I in this invention may be derivatised at functional groups to provide derivatives which are capable of conversion back to 20 the parent compound in vivo. Pharmacological Tests The compounds of the present invention exhibit Vla activity. They are selective inhibitors of the VIa receptor and are therefore likely to have a low potential to cause unwanted off-target related side-effects. The VIa activity may be detected as described below. 25 The human Vla receptor was cloned by RT-PCR from total human liver RNA. The coding sequence was subeloned in an expression vector after sequencing to confirm the identity of the amplified sequence. To demonstrate the affinity of the compounds from the present invention to the human Vla receptor binding studies were performed. Cell membranes were prepared from HEK293 cells transiently transfected with the expression vector and grown in 20 30 liter fermenters with the following protocol. 50g of cells are resuspended in 30 ml freshly prepared ice cold Lysis buffer (50mM HEPES, ImM EDTA, 10mM magnesium dichloride adjusted to pH= 7.4 + complete cocktail of protease inhibitor (Roche Diagnostics)). Homogenized with Polytron for 1min and sonicated on ice for 2x 2 minutes at 80% intensity (Vibracell sonicator). The preparation is centrifuged 20 min WO 2010/060836 PCT/EP2009/065354 - 36 at 500 g at 4'C, the pellet is discarded and the supernatant centrifuged Ihour at 4 3'000g at 4'C (19'000rpm). The pellet is resuspended in 12.5 ml Lysis buffer+12.5ml Sucrose 20% and homogenized using a Polytron for 1-2 min. The protein concentration is determined by the Bradford method and aliquots are stored at -80'C until use. For binding studies 60mg Yttrium 5 silicate SPA beads (Amersham) are mixed with an aliquot of membrane in binding buffer (50 mM Tris, 120mM sodium chloride, 5 mM potassium chloride, 2 mM Calcium dichloride, 10 mM magnesium dichloride) for 15 minutes with mixing. 50pl of bead/membrane mixture is then added to each well of a 96 well plate, followed by 50pl of 4 nM 3H-Vasopressin (American Radiolabeled Chemicals). For total binding measurement 1Opl of binding buffer are added to 10 the respective wells, for non-specific binding 100ptl of 8.4mM cold vasopressin and for compound testing 100pl of a serial dilution of each compound in 2% dimethyl sulfoxide. The plate is incubated 1 h at room temperature, centrifuged I min at 1 OOOg and counted on a Packard Top-Count. Non-specific binding counts are subtracted from each well and data is normalized to the maximum specific binding set at 100%. To calculate an IC 50 the curve is fitted using a non 15 linear regression model (XLfit) and the Ki is calculated using the Cheng-Prussoff equation. The following representative data show the antagonistic activity against human Vla receptor of compounds according to present invention. Ex# pKi Ex# pKi Ex# pKi Ex# pKi (hVl a) (hVl a) (hVl a) (hVla) 1 8.49 20 8.11 47 8.92 74 7.95 2 8.36 22 8.05 48 9.10 75 8.55 3 8.80 23 8.04 49 8.15 79 8.59 4 8.85 26 8.38 51 8.43 80 7.90 5 8.77 28 8.51 52 8.46 82 8.26 6 8.80 29 8.33 54 8.41 83 8.39 7 8.77 30 8.48 55 8.03 85 8.12 8 8.70 31 8.68 57 8.24 86 8.46 9 8.74 34 8.57 61 8.82 89 7.91 10 8.68 35 8.31 63 8.34 92 8.62 11 8.26 36 8.12 64 8.02 93 8.10 13 8.27 37 8.77 66 8.04 95 8.04 14 8.03 38 7.74 67 8.48 98 8.52 16 8.54 43 8.21 68 8.21 101 8.04 17 8.43 44 8.47 69 8.96 105 8.24 18 8.02 45 8.44 70 8.04 110 7.29 19 8.51 46 8.54 72 8.62 111 8.48 Table 3: human Vla pKi of selected examples WO 2010/060836 PCT/EP2009/065354 - 37 Pharmaceutical Compositions The compounds of formula I as well as their pharmaceutically usable acid addition salts can be used as medicaments, e.g. in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, drag~es, hard 5 and soft gelatine capsules, solutions, emulsions or suspensions. The administration can, however, also be effected rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions. The compounds of formula I and their pharmaceutically usable acid addition salts can be processed with pharmaceutically inert, inorganic or organic excipients for the production of 10 tablets, coated tablets, drag~es and hard gelatine capsules. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts etc can be used as such excipients e.g. for tablets, drag6es and hard gelatine capsules. Suitable excipients for soft gelatine capsules are e.g. vegetable oils, waxes, fats, semisolid and liquid polyols etc. Suitable excipients for the manufacture of solutions and syrups are e.g. water, polyols, 15 saccharose, invert sugar, glucose etc. Suitable excipients for injection solutions are e.g. water, alcohols, polyols, glycerol, vegetable oils etc.Suitable excipients for suppositories are e.g. natural or hardened oils, waxes, fats, semi-liquid or liquid polyols etc.. Moreover, the pharmaceutical preparations can contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the 20 osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances. The dosage can vary within wide limits and will, of course, be fitted to the individual requirements in each particular case. In general, in the case of oral administration a daily dosage of about 10 to 1000 mg per person of a compound of general formula I should be appropriate, 25 although the above upper limit can also be exceeded when necessary. The following examples illustrate the present invention without limiting it. All temperatures are given in degrees Celsius. Examples of compositions according to the invention are, but are not limited to: WO 2010/060836 PCT/EP2009/065354 - 38 Example A Tablets of the following composition are manufactured in the usual manner: ingredient mg/tablet 5 25 100 500 1. Compound of formula I 5 25 100 500 2. Lactose 45 105 30 150 3. Corn Starch 15 6 6 60 4. Microcrystalline Cellulose 34 30 30 450 5. Magnesium Stearate 1 1 1 1 Total 100 167 167 831 Table 4: possible tablet composition Manufacturing Procedure 5 1. Mix ingredients 1, 2, 3 and 4 and granulate with purified water. 2. Dry the granules at 50 C. 3. Pass the granules through suitable milling equipment. 4. Add ingredient 5 and mix for three minutes; compress on a suitable press. Example B-1 10 Capsules of the following composition are manufactured: ingredient 5 10 m g/capsule ___ _ 1 500 5 10 25 100 500 1. Compound of formula I 5 10 25 100 500 2. Lactose 159 155 123 148 3. Corn Starch 25 30 35 40 70 4. Talc 10 5 15 10 25 5. Magnesium Stearate 1 - 2 2 5 Total 200 200 200 300 600 Table 5: possible capsule ingredient composition Manufacturing Procedure 1. Mix ingredients 1, 2 and 3 in a suitable mixer for 30 minutes. 2. Add ingredients 4 and 5 and mix for 3 minutes. 15 3. Fill into a suitable capsule.
WO 2010/060836 PCT/EP2009/065354 - 39 The compound of formula I, lactose and corn starch are firstly mixed in a mixer and then in a comminuting machine. The mixture is returned to the mixer, the tale (and magnesium stearate) is added thereto and mixed thoroughly. The mixture is filled by machine into suitable capsules, e.g. hard gelatine capsules. 5 Example B-2 Soft Gelatine Capsules of the following composition are manufactured: ingredient mg/capsule Compound of formula I 5 Yellow wax 8 Hydrogenated Soya bean oil 8 Partially hydrogenated plant oils 34 Soya bean oil 110 Total 165 Table 6: possible soft gelatine capsule ingredient composition ingredient mg/capsule Gelatin 75 Glycerol 85 % 32 Karion 83 8 (dry matter) Titan dioxide 0.4 Iron oxide yellow 1.1 Total 116.5 Table 7: possible soft gelatine capsule composition Manufacturing Procedure 10 The compound of formula I is dissolved in a warm melting of the other ingredients and the mixture is filled into soft gelatin capsules of appropriate size. The filled soft gelatin capsules are treated according to the usual procedures.
WO 2010/060836 PCT/EP2009/065354 - 40 Example C Suppositories of the following composition are manufactured: ingredient mg/supp. Compound of formula I 15 Suppository mass 1285 Total 1300 Table 8: possible suppository composition Manufacturing Procedure 5 The suppository mass is melted in a glass or steel vessel, mixed thoroughly and cooled to 45'C. Thereupon, the finely powdered compound of formula I is added thereto and stirred until it has dispersed completely. The mixture is poured into suppository moulds of suitable size, left to cool, the suppositories are then removed from the moulds and packed individually in wax paper or metal foil. 10 Example D Injection solutions of the following composition are manufactured: ingredient mg/injection solution. Compound of formula I 3 Polyethylene Glycol 400 150 acetic acid q.s. ad pH 5.0 water for injection solutions ad 1.0 ml Table 9: possible injection solution composition Manufacturing Procedure The compound of formula I is dissolved in a mixture of Polyethylene Glycol 400 and water 15 for injection (part). The pH is adjusted to 5.0 by acetic acid. The volume is adjusted to 1.0 ml by addition of the residual amount of water. The solution is filtered, filled into vials using an appropriate overage and sterilized.
WO 2010/060836 PCT/EP2009/065354 - 41 Example E Sachets of the following composition are manufactured: ingredient mg/sachet Compound of formula I 50 Lactose, fine powder 1015 Microcrystalline cellulose (AVICEL PH 102) 1400 Sodium carboxymethyl cellulose 14 Polyvinylpyrrolidon K 30 10 Magnesiumstearate 10 Flavoring additives 1 Total 2500 Table 10: possible sachet composition Manufacturing Procedure 5 The compound of formula I is mixed with lactose, microcrystalline cellulose and sodium carboxymethyl cellulose and granulated with a mixture of polyvinylpyrrolidone in water. The granulate is mixed with magnesiumstearate and the flavoring additives and filled into sachets. Examples The following examples 1 - 97 are provided for illustration of the invention. They should 10 not be considered as limiting the scope of the invention, but merely as being representative thereof 4-Hydroxy-cyclohexanecarboxylic acid ester intermediates of formula (IV) 4-Hydroxy-cyclohexanecarboxylic acid ester 1 cis-4-Hydroxy-cyclohexanecarboxylic acid methyl ester 15 A solution of cis-4-hydroxy-cyclohexanecarboxylic acid (10.0 g, 69.4 mmol) and a catalytic amount of concentrated sulfuric acid in methanol (700 ml) was heated at reflux over night. After cooling to room temperature the reaction mixture was neutralized by the addition of solid sodium carbonate. The mixture was stirred for 30 min, filtered and concentrated in vacuo. The residue was triturated in ethyl acetate (150ml). The solids were removed by filtration. The filtrate was 20 concentrated in vacuo to give the crude product (10.3 g, 94%) as colorless oil, which was used in the following steps without further purification. MS m/e: 159 (M+H+). 4-Hydroxy-cyclohexanecarboxylic acid ester 2 trans-4-Hydroxy-cyclohexanecarboxylic acid methyl ester WO 2010/060836 PCT/EP2009/065354 - 42 The title compound was obtained as a colorless oil in 63% yield according to the procedure described for the preparation of cis-4-hydroxy-cyclohexanecarboxylic acid methyl ester using trans-4-hydroxy-cyclohexanecarboxylic acid instead of cis-4-hydroxy-cyclobexanecarboxylic acid. MS (El) m/e: 159 (M+, 1%), 140 (M+-H 2 0, 45%) 5 4-Arvloxy-cyclohexanecarboxylic acid ester intermediates of formula (VI) General procedure I: Etherification under Mitsunobu conditions To a solution of triphenylphosphine (1.2 eq) in dry tetrahydrofuran (0.1 M) is added diethyl azodicarboxylate (1.2 eq) at 0 'C. After 20 min a phenol derivative of formula (V) (1.2 eq) and a solution of a 4-hydroxy-cyclohexanecarboxylic acid ester of formula (IV) in tetrahydrofuran (1-3 10 M) are added consecutively at 5 'C. After completed addition the cooling bath is removed and the reaction mixture is allowed to warm to room temperature and stirred for 3-18 h. The solvent is evaporated and the residue is dissolved in ethyl acetate. The ethyl acetate solution is washed with one to two portions of 1 M aqueous sodium hydroxide solution. The aqueous layer is extracted with one to two portions of ethyl acetate. The combined organic layers are dried over 15 anhydrous sodium sulfate and concentrated in vacuo. Purification by flash-chromatography gives a 4-aryloxy-cyclohexanecarboxylic acid ester of formula (VI). General procedure II: Sodium methanesulfinate mediated arylation To a solution of a 4-hydroxy-cyclohexanecarboxylic acid ester of formula (IV) (1 eq) and a heteroaryl chloride derivative (1 eq) in dry N,N-dimethylformamide (1 M) are added 20 consecutively sodium methanesulfinate (85%, 0.25 - 1 eq) and potassium carbonate (1.5 eq). After completed addition the reaction mixture is stirred at 120 'C for 3-18 h. After cooling to room temperature the reaction mixture is partitioned between tert-butyl methyl ether and water. The layers are separated and the aqueous layer is extracted with one to two portions of tert-butyl methyl ether. The combined organic layers are washed with one to two portions of water, dried 25 over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash-chromatography gives a 4-heteroaryloxy-cyclohexanecarboxylic acid ester of formula (VI-a). General procedure III: Copper catalyzed arylation To a mixture of cuprous iodide (0.1 eq), 1, 10-phenanthroline (0.2 eq) and a heteroaryl chloride derivative (1 eq) in toluene (2 M) are added a 4-hydroxy-cyclohexanecarboxylic acid ester of 30 formula (IV) (1 eq) and cesium carbonate (2 eq). The reaction mixture is heated at reflux for 20 h. After cooling to room temperature the reaction mixture is partitioned between ethyl acetate and water. The layers are separated and the aqueous layer is extracted with one to two portions of ethyl acetate. The combined organic layers are washed with one to two portions of 0.5 aqueous hydrogen chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo.
WO 2010/060836 PCT/EP2009/065354 - 43 Purification by flash-chromatography gives a 4-heteroaryloxy-cyclohexanecarboxylic acid ester of formula (VI-a). 4-Aryloxy-cyclohexanecarboxylic acid ester 1 trans-4-Phenoxy-cyclohexanecarboxylic acid methyl ester 5 The title compound was obtained as colorless oil in 23% yield according to general procedure I. Phenol: Phenol 4-Hydroxy-cyclohexanecarboxylic acid ester: cis-4-Hydroxy-cyclohexanecarboxylic acid methyl ester MS m/e: 234 (M) 10 4-Aryloxy-cyclohexanecarboxylic acid ester 2 cis-4-Phenoxy-cyclohexanecarboxylic acid methyl ester The title compound was obtained as colorless oil in 54% yield according to general procedure I. Phenol: Phenol 4-Hydroxy-cyclohexanecarboxylic acid ester: trans-4-Hydroxy-cyclohexanecarboxylic acid 15 methyl ester MS m/e: 234 (M) 4-Aryloxy-cyclohexanecarboxylic acid ester 3 trans-4-(4-Fluoro-phenoxy)-cyclohexanecarboxylic acid methyl ester The title compound was obtained as pink oil in 29% yield according to general procedure I. 20 Phenol: 4-Fluorophenol 4-Hydroxy-cyclohexanecarboxylic acid ester: cis-4-Hydroxy-cyclohexanecarboxylic acid methyl ester MS m/e: 252 (Mm) 4-Aryloxy-cyclohexanecarboxylic acid ester 4 25 trans-4-(4-Cyano-phenoxy)-cyclohexanecarboxylic acid methyl ester The title compound was obtained according to general procedure I. Phenol: 4-Hydroxybenzonitrile 4-Hydroxy-cyclohexanecarboxylic acid ester: cis-4-Hydroxy-cyclohexanecarboxylic acid methyl ester 30 MS m/e: 260 (M+H) 4-Aryloxy-cyclohexanecarboxylic acid ester 5 trans-4-(4-Trifluoromethyl-phenoxy)-cyclohexanecarboxylic acid methyl ester The title compound was obtained according to general procedure I. Phenol: 4-Trifluoromethyl-phenol WO 2010/060836 PCT/EP2009/065354 - 44 4-Hydroxy-cyclohexanecarboxylic acid ester: cis-4-Hydroxy-cyclohexanecarboxylic acid methyl ester MS m/e: 303 (M+H) 4-Aryloxy-cyclohexanecarboxylic acid ester 6 5 trans-4-(3-Chloro-phenoxy)-cyclohexanecarboxylic acid methyl ester The title compound was obtained as colorless oil in 38% yield according to general procedure I Phenol: 3-Chlorophenol 4-Hydroxy-cyclohexanecarboxylic acid ester: cis-4-Hydroxy-cyclohexanecarboxylic acid methyl ester 10 MS m/e: 268 (M) 4-Aryloxy-cyclohexanecarboxylic acid ester 7 trans-4-(3-Methoxy-phenoxy)-cyclohexanecarboxylic acid methyl ester The title compound was obtained as pink oil in 33% yield according to general procedure I. Phenol: 3-Methoxyphenol 15 4-Hydroxy-cyclohexanecarboxylic acid ester: cis-4-Hydroxy-cyclohexanecarboxylic acid methyl ester MS m/e: 265 (M+HV) 4-Aryloxy-cyclohexanecarboxylic acid ester 8 trans-4-(3-Cyano-phenoxy)-cyclohexanecarboxylic acid methyl ester 20 The title compound was obtained as white solid in 29% yield according to general procedure I. Phenol: 3-Hydroxypyridine 4-Hydroxy-cyclohexanecarboxylic acid ester: cis-4-Hydroxy-cyclohexanecarboxylic acid methyl ester MS m/e: 259 (M+H ) 25 4-Aryloxy-cyclohexanecarboxylic acid ester 9 trans-4-m-Tolyloxy-cyclohexanecarboxylic acid methyl ester The title compound was obtained according to general procedure I. Phenol: 3-Methylphenol 4-Hydroxy-cyclohexanecarboxylic acid ester: cis-4-Hydroxy-cyclohexanecarboxylic acid methyl 30 ester MS m/e: 248 (M ) 4-Aryloxy-cyclohexanecarboxylic acid ester 10 trans-4-(3-tert-Butyl-phenoxy)-cyclohexanecarboxylic acid methyl ester The title compound was obtained according to general procedure I.
WO 2010/060836 PCT/EP2009/065354 - 45 Phenol: 3-tert-Butylphenol 4-Hydroxy-cyclohexanecarboxylic acid ester: cis-4-Hydroxy-cyclohexanecarboxylic acid methyl ester MS m/e: 291 (M+H ) 5 4-Aryloxy-cyclohexanecarboxylic acid ester 11 trans-4-(3-Trifluoromethyl-phenoxy)-cyclohexanecarboxylic acid methyl ester The title compound was obtained according to general procedure I. Phenol: 3-Trifluoromethylphenol 4-Hydroxy-cyclohexanecarboxylic acid ester: cis-4-Hydroxy-cyclohexanecarboxylic acid methyl 10 ester MS m/e: 302 (M+H -) 4-Aryloxy-cyclohexanecarboxylic acid ester 12 trans-4-(2-Fluoro-phenoxy)-cyclohexanecarboxylic acid methyl ester The title compound can be obtained according to general procedure I. 15 Phenol: 4-Fluorophenol 4-Hydroxy-cyclohexanecarboxylic acid ester: cis-4-Hydroxy-cyclohexanecarboxylic acid methyl ester 4-Aryloxy-cyclohexanecarboxylic acid ester 13 trans-4-(2-Cyano-phenoxy)-cyclohexanecarboxylic acid methyl ester 20 The title compound was obtained as pink solid in 34% yield according to general procedure I. Phenol: 2-Hydroxybenzonitrile 4-Hydroxy-cyclohexanecarboxylic acid ester: cis-4-Hydroxy-cyclohexanecarboxylic acid methyl ester MS m/e: 260 (M+H ) 25 4-Aryloxy-cyclohexanecarboxylic acid ester 14 trans-4-o-Tolyloxy-cyclohexanecarboxylic acid methyl ester The title compound was obtained as colorless oil in 15% yield according to general procedure I. Phenol: 2-Methylphenol 4-Hydroxy-cyclohexanecarboxylic acid ester: cis-4-Hydroxy-cyclohexanecarboxylic acid methyl 30 ester MS m/e: 248 (M*) 4-Aryloxy-cyclohexanecarboxylic acid ester 15 trans-4-(3,5-Difluoro-phenoxy)-cyclohexanecarboxylic acid methyl ester WO 2010/060836 PCT/EP2009/065354 - 46 The title compound was obtained as off-white solid in 22% yield according to general procedure I. Phenol: 3,5-Difluorophenol 4-Hydroxy-cyclohexanecarboxylic acid ester: cis-4-Hydroxy-cyclohexanecarboxylic acid methyl 5 ester 4-Aryloxy-cyclohexanecarboxylic acid ester 16 trans-4-(Naphthalen-2-yloxy)-cyclohexanecarboxylic acid methyl ester The title compound was obtained as yellow solid in 20% yield according to general procedure I. Phenol: 2-Naphthol 10 4-Hydroxy-cyclohexanecarboxylic acid ester: cis-4-Hydroxy-cyclohexanecarboxylic acid methyl ester MS m/e: 284 (M) 4-Aryloxy-cyclohexanecarboxylic acid ester 17 trans-4-(Naphthalen-1-yloxy)-cyclohexanecarboxylic acid methyl ester 15 The title compound was obtained as yellow solid in 20% yield according to general procedure I. Phenol: 1-Naphthol 4-Hydroxy-cyclohexanecarboxylic acid ester: cis-4-Hydroxy-cyclohexanecarboxylic acid methyl ester MS m/e: 284 (Mm) 20 4-Aryloxy-cyclohexanecarboxylic acid ester 18 trans-4-(Pyridin-3-vloxy)-cyclohexanecarboxylic acid methyl ester The title compound was obtained as white solid in 25% yield according to general procedure I. Phenol: 3-Hydroxypyridine 4-Hydroxy-cyclohexanecarboxylic acid ester: cis-4-Hydroxy-cyclohexanecarboxylic acid methyl 25 ester MS m/e: 236 (M+HV) 4-Aryloxy-cyclohexanecarboxylic acid ester 19 trans-4-(5-Chloro-pyridin-3-yloxy)-cyclohexanecarboxylic acid methyl ester The title compound was obtained as off-white solid in 29% yield according to general procedure 30 I. Phenol: 3-Chloro-5-hydroxypyridine 4-Hydroxy-cyclohexanecarboxylic acid ester: cis-4-Hydroxy-cyclohexanecarboxylic acid methyl ester MS m/e: 270 (M+H) WO 2010/060836 PCT/EP2009/065354 - 47 4-Aryloxy-cyclohexanecarboxylic acid ester 20 trans-4-(Pyridin-2-yloxy)-cyclohexanecarboxylic acid methyl ester The title compound was obtained as light red solid in 36%o yield according to general procedure I. Phenol: 2-Hydroxypyridine 5 4-Hydroxy-cyclohexanecarboxylic acid ester: cis-4-Hydroxy-cyclohexanecarboxylic acid methyl ester MS m/e: 236 (M+H*) 4-Aryloxy-cyclohexanecarboxylic acid ester 21 trans-4-(6-Chloro-pyridin-2-yloxy)-cyclohexanecarboxylic acid methyl ester 10 The title compound was obtained according to general procedure I. Phenol: 6-Chloro-pyridin-2-ol 4-Hydroxy-cyclohexanecarboxylic acid ester: cis-4-Hydroxy-cyclohexanecarboxylic acid methyl ester MS m/e: 270 (M+H-) 15 4-Aryloxy-cyclohexanecarboxylic acid ester 22 trans-4-(5-Chloro-pyridin-2-yloxy)-cyclohexanecarboxylic acid methyl ester The title compound was obtained according to general procedure I. Phenol: 5-Chloro-pyridin-2-ol 4-Hydroxy-cyclohexanecarboxylic acid ester: cis-4-Hydroxy-cyclohexanecarboxylic acid methyl 20 ester MS m/e: 270 (M+HH) 4-Aryloxy-cyclohexanecarboxylic acid ester 23 trans-4-(2,6-Dimethyl-pyrimidin-4-yloxy)-cyclohexanecarboxylic acid methyl ester The title compound was obtained as light yellow oil in 32% yield according to general procedure 25 I. Phenol: 2,4-Dimethyl-6-hydroxypyrimidine 4-Hydroxy-cyclohexanecarboxylic acid ester: cis-4-Hydroxy-cyclohexanecarboxylic acid methyl ester MS m/e: 265 (M+H*) 30 4-Aryloxy-cyclohexanecarboxylic acid ester 24 cis/trans-4-(Pyrimidin-2-yloxy)-cyclohexanecarboxylic acid ethyl ester (1:2) The title compound was obtained as yellow amorphous solid in 24% yield according to general procedure III. Heteroaryl chloride: 2-Chloropyrimidine WO 2010/060836 PCT/EP2009/065354 - 48 4-Hydroxy-cyclohexanecarboxylic acid ester: cis/trans-4-Hydroxy-cyclohexanecarboxylic acid ethyl ester (2 :1) MS m/e: 251 (M+Hv) 4-Aryloxy-cyclohexanecarboxylic acid ester 25 5 cis/trans-4-(Pyrazin-2-yloxy)-cyclohexanecarboxylic acid ethyl ester (1:1) The title compound was obtained as white solid in 15% yield according to general procedure II. Heteroaryl chloride : 2-Chloropyrazine 4-Hydroxy-cyclohexanecarboxylic acid ester: cis/trans-4-Hydroxy-cyclohexanecarboxylic acid ethyl ester ester (2 :1) 10 MS m/e: 251 (M+H ) 4-Aryloxy-cyclohexanecarboxylic acid ester 26 cis/trans-4-(6-Chloro-pyrimidin-4-yloxy)-cyclohexanecarboxylic acid ethyl ester (1:1) The title compound was obtained as colorless oil in 38% yield according to general procedure III. Heteroaryl chloride : 4,6-Dichloropyrimidine 15 4-Hydroxy-cyclohexanecarboxylic acid ester: cis/trans-4-Hydroxy-cyclohexanecarboxylic acid ethyl ester ester (2 :1) MS m/e: 284 (M) 4-Aryloxy-cyclohexanecarboxylic acid ester 27 cis/trans-4-(Pyrimidin-4-yloxy)-cyclohexanecarboxylic acid ethyl ester (1:1) 20 To an argon purged solution of cis/trans-4-(6-chloro-pyrimidin-4-yloxy)-cyclohexanecarboxylic acid ethyl ester (1:1) (1.05 g, 3.69 mmol) and triethylamine (0.52 ml, 3.69 mmol) in ethyl acetate (37 ml) was added palladium on charcoal 10% (0.078 g). The reaction mixture was purged with hydrogen gas and stirred under an atmosphere of hydrogen gas for 16 h at room temperature. The catalyst and the ammonium salts were removed by filtration over Decalite. The filtrate was 25 concentrated in vacuo to give the title compound (0.92 g) as light yellow oil in quantitative yield. MS m/e: 251 (M+HV). 4-Aryloxy-cyclohexanecarboxylic acid ester 28 cis/trans-4-(6-Chloro-pyridazin-3-yloxy)-cyclohexanecarboxylic acid ethyl ester (1:1) The title compound was obtained as white solid in 39% yield according to general procedure III. 30 Heteroaryl chloride : 3,6-Dichloropyridazine 4-Hydroxy-cyclohexanecarboxylic acid ester: cis/trans-4-Hydroxy-cyclohexanecarboxylic acid ethyl ester (2 :1) MS m/e: 285 (M+H) 4-Aryloxy-cyclohexanecarboxylic acid ester 29 WO 2010/060836 PCT/EP2009/065354 - 49 cis/trans-4-(Pyridazin-3-yloxy)-cyclohexanecarboxylic acid ethyl ester (1:1) To an argon purged solution of cis/trans-4-(6-chloro-pyridazin-3-yloxy)-cyclohexanecarboxylic acid ethyl ester (1:1) (1.30 g, 4.57 mmol) and triethylamine (0.64 ml, 4.57 mmol) in ethyl acetate (46 ml) was added palladium on charcoal 10% (0.097 g). The reaction mixture was purged with 5 hydrogen gas and stirred under an atmosphere of hydrogen gas for 4 h at room temperature. The catalyst and the ammonium salts were removed by filtration over Decalite. The filtrate was concentrated in vacuo to give the title compound (1.09 g, 9 5 %) as light yellow oil. MS m/e: 251 (M+H*) 4-Aryloxy-cyclohexanecarboxylic acid ester 30 10 trans-4-(3-Fluoro-pyridin-2-yloxy)-cyclohexanecarboxylic acid methyl ester The title compound was obtained according to general procedure I. Phenol: 3-Fluoro-2-hydroxypyridine 4-Hydroxy-cyclohexanecarboxylic acid ester: cis-4-Hydroxy-cyclohexanecarboxylic acid methyl ester 15 MS m/e: 253 (M) 4-Aryloxy-cyclohexanecarboxylic acid ester 31 trans-4-(3-Fluoro-pyridin-2-yloxy)-cyclohexanecarboxylic acid methyl ester The title compound was obtained according to general procedure I. Phenol: 5-Fluoro-2-hydroxypyridine 20 4-Hydroxy-cyclohexanecarboxylic acid ester: cis-4-Hydroxy-cyclohexanecarboxylic acid methyl ester MS m 1 e: 254 (M+H ) 4-Aryloxy-cyclohexanecarboxylic acid ester 32 trans-4-(3-Fluoro-pyridin-2-yloxy)-cyclohexanecarboxylic acid methyl ester 25 The title compound was obtained according to general procedure I. Phenol: 2-Hydroxy-6-methylpyridine 4-Hydroxy-cyclohexanecarboxylic acid ester: cis-4-Hydroxy-cyclohexanecarboxylic acid methyl ester MS m/e: 250 (M+H) 30 4-Aryloxy-cyclohexanecarboxylic acid ester 33 cis-4-(Pyridin-2-yloxy)-cyclohexanecarboxylic acid methyl ester The title compound was obtained according to general procedure I. Phenol: 2-Hydroxypyridine WO 2010/060836 PCT/EP2009/065354 - 50 4-Hydroxy-cyclohexanecarboxylic acid ester: trans-4-Hydroxy-cyclohexanecarboxylic acid methyl ester MS m/e: 236 (M+H) 4-Arvloxy-cyclohexanecarboxylic acid intermediates of formula (VIII) 5 4-Aryloxy-cyclohexanecarboxylic acid 1 cis/trans-4-(Pyrimidin-2-yloxy)-cyclohexanecarboxylic acid (1:2) To a solution of cis/trans-4-(pyrimidin-2-yloxy)-cyclohexanecarboxylic acid ethyl ester (1:2) (0.35 g, 1.4 mmol) in 1,4-dioxan (7 ml) was added 2 M aqueous sodium hydroxide solution (7.0 ml, 14 mmol). Stirring at room temperature for 16 h was followed by acidification to pH 2-3 10 with 0.5 M aqueous hydrogen chloride solution (50 ml) and extraction with three 100-ml portions of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound (0.26 g, 83%) as yellow oil. MS m/e: 221 (M-H). 4-Aryloxy-cyclohexanecarboxylic acid 2 15 cis/trans-4-(Pyrimidin-4-yloxy)-cyclohexanecarboxylic acid (1:1) To a solution of cis/trans-4-(pyrimidin-4-yloxy)-cyclohexanecarboxylic acid ethyl ester (1:1) (0.90 g, 3.6 mmol) in 1,4-dioxane (18 ml) was added 2 M aqueous sodium hydroxide solution (18 ml, 36 mmol). Stirring at room temperature for 3 h was followed by acidification to pH 2-3 with 1 M aqueous hydrogen chloride solution (42 ml) and extraction with four 100-ml portions 20 of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound (0.76 g, 95%) as white solid. MS m 1 e: 221 (M-H). 4-Aryloxy-cyclohexanecarboxylic acid 3 cis/trans-4-(Pyridazin-3-yloxy)-cyclohexanecarboxylic acid (1:1) 25 To a solution of cis/trans-4-(pyridazin-3-yloxy)-cyclohexanecarboxylic acid ethyl ester (1:1) (1.05 g, 4.19 mmol) in 1,4-dioxane (21 ml) was added 2 M aqueous sodium hydroxide solution (21 ml, 42 mmol). Stirring at room temperature for 16 h was followed by acidification to pH 2-3 with 1 M aqueous hydrogen chloride solution (44 ml) and extraction with three 100-ml portions of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and 30 concentrated in vacuo to give the title compound (0.80 g, 86%) as off-white solid. MS m/e: 221 (M-H+). Hydrazide intermediates of formula (II) General procedure IV: Conversion of ester to hydrazide WO 2010/060836 PCT/EP2009/065354 -51 A mixture of 4-(aryloxy)-cyclohexanecarboxylic acid ester of formula (VI) (1 eq) and hydrazine hydrate (5 eq) is heated at 120 'C for 5 h. After cooling to room temperature the reaction mixture is partitioned between dichloromethane and water. The layers are separated and the organic layer is washed with water and brine. The organic layer is dried over anhydrous sodium sulfate and 5 concentrated in vacuo to give the crude title compound, which is used in the next step without further purification. Hydrazide 1 trans-4-Phenoxy-cyclohexanecarboxylic acid hydrazide A mixture of trans-4-phenoxy-cyclohexanecarboxylic acid methyl ester (1.07 g, 4.57 mmol) and 10 hydrazine hydrate (0.22 g, 4.48 mmol) was heated at 120 'C for 4 h. After cooling to room temperature the reaction mixture was concentrated in vacuo to give the crude title compound as white solid in quantitative yield, which was used in the next step without further purification. MS m/e: 235 (M+Hv). Hydrazide 2 15 cis-4-Phenoxy-cyclohexanecarboxylic acid hydrazide A mixture of cis-4-phenoxy-cyclohexanecarboxylic acid methyl ester (0.55 g, 2.3 mmol) and hydrazine hydrate (0.11 g, 2.3 mmol) was heated at 120 'C for 24 h. After cooling to room temperature the reaction mixture was suspended in toluene (70 ml). After evaporation of the solvent, the residue was suspended in toluene (70 ml) again. The solvent was evaporated and the 20 residue was dried in high vacuo (1-2 mbar) to give the crude title compound (0.50 g, 92%) as light yellow foam, which was used in the next step without further purification. MS m 1 e: 235 (M+H). Hydrazide 3 trans-4-(4-Fluoro-phenoxy)-cyclohexanecarboxylic acid hydrazide 25 A mixture of trans-4-(4-fluoro-phenoxy)-cyclohexanecarboxylic acid methyl ester (0.23 g, 0.93 mmol) and hydrazine hydrate (0.046 g, 0.91 mmol) was heated at 120 'C for 3.5 h. After cooling to room temperature the reaction mixture was suspended in toluene (70 ml). After evaporation of the solvent, the residue was suspended in toluene (70 ml) again. The solvent was evaporated and the residue was dried in high vacuo (1-2 mbar) to give the crude title compound (0.22 g, 96%) as 30 white solid, which was used in the next step without further purification. MS m/e: 253 (M+H). Hydrazide 4 trans-4-(4-Cyano-phenoxy)-cyclohexanecarboxylic acid hydrazide The title compound was obtained from trans-4-(4-cyano-phenoxy)-cyclohexanecarboxylic acid methyl ester according to general procedure IV. MS m/e: 260 (M+H+).
WO 2010/060836 PCT/EP2009/065354 - 52 Hydrazide 5 trans-4-(4-Trifluoromethyl-phenoxy)-cyclohexanecarboxylic acid hydrazide The title compound was obtained from trans-4-(4-trifluoromethyl-phenoxy) cyclohexanecarboxylic acid methyl ester according to general procedure IV. 5 MS m/e: 303 (M+-H) Hydrazide 6 trans-4-(3-Chloro-phenoxy)-cyclohexanecarboxylic acid hydrazide A mixture of trans-4-(3-chloro-phenoxy)-cyclohexanecarboxylic acid methyl ester (0.25 g, 0.93 mmol) and hydrazine hydrate (0.044 ml, 0.91 mmol) was heated at 120 'C for 22 h. Addition of 10 further hydrazine hydrate (0.020 ml, 0.42 mmol) was followed by stirring at 120 'C for 5 h. After cooling to room temperature the reaction mixture was partitioned between ethyl acetate (50 ml) and 1 M aqueous sodium hydroxide solution (50 ml). The layers were separated and the aqueous layer was extracted with a 50-ml portion of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude title 15 compound (0.21 g, 86%) as white solid, which was used in the next step without further purification. MS m/e: 269 (M+H) Hydrazide 7 trans-4-(3-Methoxy-phenoxy)-cyclohexanecarboxylic acid hydrazide A mixture of trans-4-(3-methoxy-phenoxy)-cyclohexanecarboxylic acid methyl ester (0.20 g, 20 0.75 mmol) and hydrazine hydrate (0.035 ml, 0.73 mmol) was heated at 120 'C for 22 h. After cooling to room temperature the reaction mixture was partitioned between ethyl acetate (50 ml) and 1 M aqueous sodium hydroxide solution (50 ml). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude title compound (0.18 g, 92%) as white solid, which was used in the next step without further purification. 25 MS m/e: 265 (M+Hv) Hydrazide 8 trans-4-(3-Cyano-phenoxy)-cyclohexanecarboxylic acid hydrazide A mixture of trans-4-(3-cyano-phenoxy)-cyclohexanecarboxylic acid methyl ester (0.277 g, 1.07 mmol) and hydrazine hydrate (0.104 ml, 2.14 mmol) in n-butanol (0.5 ml) was heated at 120 'C 30 for 18 h. After cooling to room temperature the reaction mixture was partitioned between ethyl acetate (50 ml) and 1 M aqueous sodium hydroxide solution (50 ml). The layers were separated and the aqueous layer was extracted with a 50-ml portion of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was triturated in methanol (7 ml). The solids were removed by filtration and the filtrate was WO 2010/060836 PCT/EP2009/065354 - 53 concentrated in vacuo to give the crude title compound (0.15 g, 55%) as light red solid, which was used in the next step without further purification. MS m/e: 260 (M+H) Hydrazide 9 trans-4-m-Tolyloxy-cyclohexanecarboxylic acid hydrazide 5 The title compound was obtained from trans-4-m-tolyloxy-cyclohexanecarboxylic acid methyl ester according to general procedure IV. MS m/e: 249 (M+H) Hydrazide 10 trans-4-(3-tert-Butyl-phenoxy)-cyclohexanecarboxylic acid hydrazide The title compound was obtained from trans-4-(3-tert-butyl-phenoxy)-cyclohexanecarboxylic 10 acid methyl ester according to general procedure IV. Hydrazide 11 trans-4-(3-Trifluoromethyl-phenoxy)-cyclohexanecarboxyic acid hydrazide The title compound was obtained from trans-4-(3-trifluoromethyl-phenoxy) cyclohexanecarboxylic acid methyl ester according to general procedure IV. 15 MS m/e: 303 (M+H ) Hydrazide 12 trans-4-(2-Fluoro-phenoxy)-cyclohexanecarboxylic acid hydrazide The title compound was obtained from trans-4-(2-fluoro-phenoxy)-cyclohexanecarboxylic acid methyl ester according to general procedure IV. 20 Hydrazide 13 trans-4-(2-Cyano-phenoxy)-cyclohexanecarboxylic acid hydrazide A mixture of trans-4-(2-cyano-phenoxy)-cyclohexanecarboxylic acid methyl ester (0.20 g, 0.77 mmol) and hydrazine hydrate (0.037 ml, 0.76 mmol) in n-butanol (0.5 ml) was heated at 120 'C for 22 h. After cooling to room temperature the reaction mixture was partitioned between ethyl 25 acetate (50 ml) and 1 M aqueous sodium hydroxide solution (50 ml). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude title compound (0.18 g, 90%) as white solid, which was used in the next step without further purification. MS m/e: 260 (M+H) Hydrazide 14 30 trans-4-o-Tolyloxy-cyclohexanecarboxylic acid hydrazide A mixture of trans-4-o-tolyloxy-cyclohexanecarboxylic acid methyl ester (0.091 g, 0.36 mmol) and hydrazine hydrate (0.02 ml, 0.36 mmol) was heated at 120 'C for 22 h. After cooling to room temperature the reaction mixture was suspended in toluene. After evaporation of the WO 2010/060836 PCT/EP2009/065354 - 54 solvent the residue was dried in high vacuo (1-2 mbar) to give the crude title compound (0.73 g, 81%) as white solid, which was used in the next step without further purification. MS m/e: 249 (M+Hv) Hydrazide 15 5 trans-4-(3,5-Difluoro-phenoxy)-cvclohexanecarboxylic acid hydrazide A mixture of trans-4-(3,5-difluoro-phenoxy)-cyclohexanecarboxylic acid methyl ester (0.148 g, 0.548 mmol) and hydrazine hydrate (0.106 ml, 2.19 mmol) was heated at 120 'C for 18 h. After cooling to room temperature the reaction mixture was partitioned between ethyl acetate (50 ml) and 1 M aqueous sodium hydroxide solution (50 ml). The organic layer was separated. The 10 aqueous layer was extracted with one portion of ethyl acetate (50 ml). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude title compound (0.14 g, 96%) as light yellow solid, which was used in the next step without further purification. MS m/e: 271 (M+H) Hydrazide 16 15 trans-4-(Naphthalen-2-yloxy)-cyclohexanecarboxylic acid hydrazide A mixture of trans-4-(naphthalen-2-yloxy)-cyclohexanecarboxylic acid methyl ester (0.130 g, 0.457 mmol) and hydrazine hydrate (0.02 ml, 0.45 mmol) in methanol (0.5 ml) was heated at 80 'C for 16 h. After cooling to room temperature the reaction mixture was partitioned between ethyl acetate (50 ml) and 1 M aqueous sodium hydroxide solution (50 ml). The organic layer was 20 separated, dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude title compound (0.112 g, 86%) as yellow solid, which was used in the next step without further purification. MS m/e: 285 (M+H) Hydrazide 17 trans-4-(Naphthalen-1-yloxy)-cyclohexanecarboxylic acid hydrazide 25 A mixture of trans-4-(naphthalen-1-yloxy)-cyclohexanecarboxylic acid methyl ester (0.130 g, 0.457 mmol) and hydrazine hydrate (0.022 ml, 0.45 mmol) in methanol (0.5 ml) was heated at 80 'C for 16 h. After cooling to room temperature the reaction mixture was partitioned between ethyl acetate (50 ml) and 1 M aqueous sodium hydroxide solution (50 ml). The organic layer was separated. The aqueous layer was extracted with two 50-ml portions of ethyl acetate. The 30 combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give a 3:1 mixture of the crude title compound and starting material. This mixture (0.12 g) and hydrazine hydrate (0.022 ml, 0.45 mmol) were dissolved in 1,4-dioxane (0.4 ml) and heated at reflux for 18 h. After cooling to room temperature the reaction mixture was partitioned between ethyl acetate (50 ml) and 1 M aqueous sodium hydroxide solution (50 ml). The organic layer was WO 2010/060836 PCT/EP2009/065354 - 55 separated. The aqueous layer was extracted with two 50-ml portions of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude title compound (0.120 g, 83%) as yellow solid with a purity of 90%, which was used in the next step without further purification. MS m/e: 285 (M+H) 5 Hydrazide 18 trans-4-(Pyridin-3-yloxy)-cyclohexanecarboxylic acid hydrazide A mixture of trans-4-(pyridin-3-yloxy)-cyclohexanecarboxylic acid methyl ester (0.141 g, 0.599 mmol) and hydrazine hydrate (0.029 ml, 0.59 mmol) in n-butanol (0.5 ml) was heated at 120 'C for 22 h. After cooling to room temperature the reaction mixture was partitioned between ethyl 10 acetate (50 ml) and 1 M aqueous sodium hydroxide solution (50 ml). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude title compound (0.061 g, 43%) as white solid, which was used in the next step without further purification. MS m/e: 236 (M+H) Hydrazide 19 15 trans-4-(5-Chloro-pyridin-3-yoxy)-cyclohexanecarboxylic acid hydrazide A mixture of trans-4-(5-chloro-pyridin-3-yloxy)-cyclohexanecarboxylic acid methyl ester (0.19 g, 0.70 mmol) and hydrazine hydrate (0.14 ml, 2.8 mmol) in n-butanol (0.5 ml) was heated at 120 'C for 18 h. After cooling to room temperature the reaction mixture was triturated in toluene (100 ml). The product was collected by filtration and dried in vacuo to give the crude title 20 compound (0.15 g, 79%) as white solid, which was used in the next step without further purification. MS m/e: 270 (M+H) Hydrazide 20 trans-4-(Pyridin-2-yloxy)-cyclohexanecarboxylic acid hydrazide A mixture of trans-4-(pyridin-2-yloxy)-cyclohexanecarboxylic acid methyl ester (1.33 g, 5.66 25 mmol) and hydrazine hydrate (0.55 ml, 11 mmol) in n-butanol (1 ml) was heated at 120 'C for 68 h. After cooling to room temperature the reaction mixture was evaporated and dried in high vacuo (ca. 1-2 mbar) at 100 'C for 2 h to give the crude title compound (1.28 g, 96%) as white solid, which was used in the next step without further purification. MS m/e: 236 (M+H*) Hydrazide 21 30 trans-4-(6-Chloro-pyridin-2-yloxy)-cyclohexanecarboxylic acid hydrazide The title compound was obtained from trans-4-(6-chloro-pyridin-2-yloxy) cyclohexanecarboxylic acid methyl ester according to general procedure IV. MS m 1 e: 270 (M+H+) Hydrazide 22 WO 2010/060836 PCT/EP2009/065354 -56 trans-4-(5-Chloro-pyridin-2-yoxy)-cyclohexanecarboxylic acid hydrazide The title compound was obtained from trans-4-(5-chloro-pyridin-2-yloxy) cyclohexanecarboxylic acid methyl ester according to general procedure IV. Hydrazide 23 5 trans-4-(2,6-Dimethyl-pyrimidin-4-yoxy)-cyclohexanecarboxylic acid hydrazide A mixture of trans-4-(2,6-dimethyl-pyrimidin-4-yloxy)-cyclohexanecarboxylic acid methyl ester (0.20 g, 0.76 mmol) and hydrazine hydrate (0.15 ml, 3.0 mmol) in n-butanol (0.5 ml) was heated at reflux over night. The reaction mixture was evaporated and dried in high vacuo (ca. 1-2 mbar) to give the crude title compound (0.19 g, 95%) as white solid, which was used in the next step 10 without further purification. MS m/e: 265 (M+H) Hydrazide 24 cis/trans-4-(Pyrimidin-2-yloxy)-cyclohexanecarboxylic acid hydrazide (1:2) To a solution of cis/trans-4-(pyrimidin-2-yloxy)-cyclohexanecarboxylic acid (1:2) (0.258 g, 1.16 mmol) and triethylamine (0.162 ml, 1.16 mmol) in THF (6 ml) was added ethyl chloroformate 15 (0.111 ml, 1.16 mmol) at 0 'C. The reaction mixture was stirred for 1 h. The ammonium salts were removed by filtration. The filtrate was added to a cold solution of hydrazine hydrate (0.116 g, 2.32 mmol) in methanol (10 ml). The reaction mixture was stirred for 2 h at room temperature and then partitioned between ethyl acetate (50 ml) and a mixture of a 1:1 mixture of 1 M aqueous sodium hydroxide solution and brine (50 ml). The layers were separated. The aqueous 20 layer was extracted with five 50-ml portions of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude title compound (0.177 g, 65%) as white solid, which was used in the next step without further purification. MS m/e: 237 (M+HV) Hydrazide 25 25 trans-4-(Pyrazin-2-yoxy)-cyclohexanecarboxylic acid hydrazide A mixture of cis/trans-4-(pyrazin-2-yloxy)-cyclohexanecarboxylic acid ethyl ester (1.11 g, 4.41 mmol) and hydrazine hydrate (0442 g, 8.83 mmol) was heated at 120 'C for 72 h. After cooling to room temperature the reaction mixture was partitioned between ethyl acetate (50 ml) and water (30 ml). The organic layer was separated. The aqueous layer was extracted with two 50 ml 30 portions of ethyl acetate. The combined organic layers were washed with brine (30 ml), dried over anhydrous sodium sulfate and concentrated in vacuo. The crude cis/trans-hydrazide was triturated in ethyl acetate (5 ml). The precipitate was collected by filtration and dried in vacuo to give the crude title compound (0.236 g, 23%) as white solid, which was used in the next step without further purification. MS m/e: 237 (M+H+) WO 2010/060836 PCT/EP2009/065354 - 57 Hydrazide 26 cis/trans-4-(Pyrimidin-4-yloxy)-cyclohexanecarboxylic acid hydrazide (1:1) To a solution of cis/trans-4-(pyrimidin-4-yloxy)-cyclohexanecarboxylic acid (1:1) (0.750 g, 3.37 mmol) and triethylamine (0.470 ml, 3.37 mmol) in THF (16 ml) was added ethyl chloroformate 5 (0.322 ml, 3.37 mmol) at 0 'C. The reaction mixture was stirred for 1 h. The ammonium salts were removed by filtration. The filtrate was added to a cold solution of hydrazine hydrate (0.338 g, 6.75 mmol) in methanol (20 ml). The reaction mixture was stirred for 2 h at room temperature. The solvent was evaporated under reduced pressure and the residue was partitioned between ethyl acetate (100 ml) and a 1:1 mixture of 1 M aqueous sodium hydroxide solution and brine 10 (30 ml). The organic layer was separated. The aqueous layer was extracted with three 100-ml portions of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude title compound (0.588 g, 74%) as off-white solid, which was used in the next step without further purification. MS m/e: 237 (M+H) Hydrazide 27 15 cis/trans-4-(Pyridazin-3-yloxy)-cyclohexanecarboxylic acid hydrazide (1:1) To a solution of cis/trans-4-(pyridazin-3-yloxy)-cyclohexanecarboxylic acid (1:1) (0.780 g, 3.51 mmol) and triethylamine (0.489 ml, 3.37 mmol) in THF (17 ml) was added ethyl chloroformate (0.334 ml, 3.51 mmol) at 0 'C. The reaction mixture was stirred for 1 h. The ammonium salts were removed by filtration. The filtrate was added to a cold solution of hydrazine hydrate (0.351 20 g, 7.02 mmol) in methanol (20 ml). The reaction mixture was stirred for 2 h at room temperature. The solvent was evaporated under reduced pressure and the residue was partitioned between ethyl acetate (100 ml) and a 1:1 mixture of 1 M aqueous sodium hydroxide solution and brine (30 ml). The organic layer was separated. The aqueous layer was extracted with five 75-ml portions of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate 25 and concentrated in vacuo to give the crude title compound (0.580 g, 70%) as off-white solid, which was used in the next step without further purification. MS m/e: 237 (M+H) Hydrazide 28 trans-4-(3-Fluoro-pyridin-2-yloxy)-cyclohexanecarboxylic acid hydrazide A mixture of trans-4-(3-fluoro-pyridin-2-yloxy)-cyclohexanecarboxylic acid methyl ester (0.60 g, 30 2.4 mmol) and hydrazine hydrate (0.53 ml, 11 mmol) in n-butanol (1 ml) was heated at 125 'C for 4 h. After cooling to room temperature the reaction mixture was partitioned between dichloromethane (75 ml) and water (75 ml). The aqueous layer was washed with dichloromethane /75 ml). The combined organic layers were washed with water (75 ml) and brine (75 ml), dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude WO 2010/060836 PCT/EP2009/065354 - 58 title compound (0.45 g, 83%) as white solid, which was used in the next step without further purification. MS m/e: 254 (M+H') Hydrazide 29 trans-4-(5-Fluoro-pyridin-2-yloxy)-cyclohexanecarboxylic acid hydrazide 5 A mixture of trans-4-(5-fluoro-pyridin-2-yloxy)-cyclohexanecarboxylic acid methyl ester (0.92 g, 3.6 mmol) and hydrazine hydrate (0.80 ml, 16 mmol) in n-butanol (1 ml) was heated at 125 'C for 4 h. After cooling to room temperature the reaction mixture was partitioned between dichloromethane (75 ml) and water (75 ml). The aqueous layer was washed with dichloromethane /75 ml). The combined organic layers were washed with water (75 ml) and 10 brine (75 ml), dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude title compound (0.55 g, 67%) as white solid, which was used in the next step without further purification. MS m/e: 254 (M+H) Hydrazide 30 trans-4-(6-Methyl-pyridin-2-yoxy)-cyclohexanecarboxylic acid hydrazide 15 A mixture of trans-4-(6-methyl-pyridin-2-yloxy)-cyclohexanecarboxylic acid methyl ester (0.62 g, 2.5 mmol) and hydrazine hydrate (0.55 ml, 11 mmol) in n-butanol (1 ml) was heated at 125 'C for 4 h. After cooling to room temperature the reaction mixture was partitioned between dichloromethane (75 ml) and water (75 ml). The aqueous layer was washed with dichloromethane /75 ml). The combined organic layers were washed with water (75 ml) and 20 brine (75 ml), dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude title compound (0.48 g, 86%) as white solid, which was used in the next step without further purification. MS m/e: 250 (M+H) Hydrazide 31 cis-4-(Pyridin-2-yloxy)-cyclohexanecarboxylic acid hydrazide 25 A mixture of cis-4-(pyridin-2-yloxy)-cyclohexanecarboxylic acid methyl ester (0.39 g, 1.6 mmol) and hydrazine hydrate (0.40 ml, 8.2 mmol) in n-butanol (0.5 ml) was heated at 125 'C over night. After cooling to room temperature the reaction mixture was partitioned between dichloromethane (75 ml) and water (75 ml). The aqueous layer was washed with dichloromethane /75 ml). The combined organic layers were washed with water (75 ml) and 30 brine (75 ml), dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude title compound (0.35 g, 91%) as colorless oil, which was used in the next step without further purification. MS m/e: 236 (M+H) Thiolactam intermediates of formula (11) WO 2010/060836 PCT/EP2009/065354 - 59 7-Chloro-2-thioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepine-4-carboxylic acid tert-butyl ester a) 4-Chloro-2-chloromethyl- 1 -nitro-benzene To a solution of 5-chloro-2-nitrobenzyl alcohol (80 g, 0.42 mol) and triethylamine (64 ml, 0.46 5 mol) in dichloromethane (840 ml) was added drop wise thionyl chloride (34 ml, 0.46 mol) during a period of 30 min while the internal temperature was kept below 32 'C by cooling with a water bath. The reaction mixture was stirred for 3 h. The solvent was evaporated and the residue was triturated in warm tert-butyl methyl ether (970 ml). The ammonium salts were removed by filtration and the filtrate was concentrated in vacuo to give the title compound (85 g, 99%) as 10 brown oil which was used in the next step without purification. MS m/e: 205 (Mm). b) (5-Chloro-2-nitro-benzylamino)-acetic acid ethyl ester A mixture of 4-chloro-2-chloromethyl-1-nitro-benzene (85 g, 0.41 mol), glycine ethyl ester hydrochloride (70 g, 0.50 mol) and triethylamine (121.4 ml, 0.8665 mol) in ethanol (1000 ml) was heated at reflux for 8 h. The solvent was evaporated and the residue was triturated in warm 15 tert-butyl methyl ether. The ammonium salts were removed by filtration and the filtrate was concentrated in vacuo to give the title compound (111 g, 99%) as an amorphous brown solid which was used in the next step without purification. MS m/e: 273 (M+H). c) [tert-Butoxycarbonyl-(5 -chloro-2-nitro-benzyl)-amino] -acetic acid ethyl ester A solution of (5-chloro-2-nitro-benzylamino)-acetic acid ethyl ester (110 g, 0.403 mol), di-tert 20 butyl dicarbonate (180 g, 0.807 mol) and 4-N,N-dimethylaminopyridine (2.51 g, 0.0202 mol) in dichloromethane (1200 ml) was stirred for 2 h at 0 'C and further 16 h at room temperature. The solvent was evaporated and the crude product was purified by flash chromatography with a cyclohexane/ethyl acetate mixture as eluent to give the title compound (76.4 g, 51%) as light yellow viscous oil. MS m/e: 373 (M+H). 25 d) [(2-Amino-5 -chloro-benzyl)-tert-butoxycarbonyl-amino] -acetic acid ethyl ester To a solution of [tert-butoxycarbonyl-(5-chloro-2-nitro-benzyl)-amino]-acetic acid ethyl ester (69.0 g, 0.186 mol) in ethyl acetate (1200 ml) was added zinc bromide (8.5 g, 0.037 mol). The reaction mixture was purged with argon after 15 min. After addition of the palladium catalyst (10% on activated charcoal, 7.9 g, 0.0074 mol) the mixture was hydrogenated at ambient 30 pressure during a period of ca. 48 h until ca. 13 1 of hydrogen gas had been consumed. The catalyst was removed by filtration and the filtrate was washed with two portions of saturated aqueous sodium bicarbonate solution and brine, each. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound (60.6 g, 95.5%) as yellow waxy solid. MS m/e: 343 (M+H+).
WO 2010/060836 PCT/EP2009/065354 - 60 e) 7-Chloro-2-oxo-1,2,3,5-tetrahydro-benzo[1,4]diazepine-4-carboxylic acid tert-butyl ester To a solution of [(2-amino-5-chloro-benzyl)-tert-butoxycarbonyl-amino]-acetic acid ethyl ester (60 g, 0.18 mol) in tetrahydrofuran (600 ml) was added potassium tert-butoxide (22 g, 0.19 mol) in small portions at 5 'C under cooling on an ice-water batch. After completed addition the 5 cooling bath was removed and reaction mixture was stirred for 3 h at room temperature followed by addition of water (400 ml), saturated aqueous ammonium chloride solution (280 ml) and ethyl acetate (800 ml). After 10 min the precipitate was collected by filtration. The organic layer was separated from the filtrate, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was combined with the precipitate, which had previously been collected by filtration, and 10 crystallized from hot ethyl acetate to give the title compound (46 g, 88%) as white solid. MS m/e: 295 (M-H). f) 7-Chloro-2-thioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepine-4-carboxylic acid tert-butyl ester A mixture of 7-chloro-2-oxo-1,2,3,5-tetrahydro-benzo[1,4]diazepine-4-carboxylic acid tert-butyl ester (41.1 g, 0.139 mol) and 2,4-bis-(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4 15 disulfide (31.5 g, 0.0763 mol) in tetrahydrofuran (1100 ml) was heated at reflux for 3 h. The solvent was evaporated and the residue was triturated in tert-butyl methyl ether. The precipitate was removed by filtration and the filtrate was concentrated to dryness. The residue was crystallized from hot ethanol to give the title compound (37.5 g, 86.4%) as light yellow solid. MS m/e: 311 (M-H). 20 7-Fluoro-2-thioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepine-4-carboxylic acid tert-butyl ester The title compound was obtained as light yellow solid in comparable yields according to the procedures described above for the synthesis of 7-chloro-2-thioxo-1,2,3,5-tetrahydro benzo[e][1,4]diazepine-4-carboxylic acid tert-butyl ester using 5-fluoro-2-nitrobenzyl alcohol 25 instead of 5-chloro-2-nitrobenzyl alcohol in step a). MS m/e: 297 (M-H). Examples General procedure V: Condensation of hydrazide and thiolactam to triazole A mixture of a hydrazide derivative of formula (II) (1-1.5 eq) and a thiolactam of formula (III) (1 eq) in n-butanol (0.1-0.2 M) is heated at reflux for 16-72 h. After cooling to room temperature 30 the solvent is evaporated and the residue is purified by flash-chromatography to give a compound of formula (I). When a thiolactam of formula (111-1) (compounds of formula (III) in which R2 is tert-butoxycarbonyl) is used the N-tert-butoxycarbonyl group of the resulting triazole product of formula (I-a) may be partially or completely cleaved thermally, and a secondary amine derivative of formula (I-b) is obtained in addition or as the sole product.
WO 2010/060836 PCT/EP2009/065354 - 61 General procedure VI: Cleavage of N-tert-butoxycarbonyl (N-BOC) group A solution of an N-BOC derivative of general formula (I-a) (1 eq) in 1.25 M methanolic or 1.5 M ethanolic hydrogen chloride solution (10 - 20 eq HCI) is heated at 50 'C for 15-60 min. After cooling to room temperature the reaction mixture is concentrated in vacuo to give a secondary 5 amine derivative of general formula (I-b) as hydrochloride salt. Optionally the free base can be obtained by partitioning the hydrochloride salt between 1 M aqueous sodium hydroxide solution and an organic solvent, e.g. ethyl acetate or dichloromethane. The layers are separated and the aqueous layer is extracted with two portions of the organic solvent. The combined organic layers are dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the free base 10 of a compound of formula (I-b). General procedure VII: Reductive N-alkylation A mixture of a compound of formula (I-b) as free base or as hydrochloride salt (1 eq, 0.1-0.2 M), triethylamine (1 eq when the hydrochloride salt of a compound of formula (I-b) is used) and an aldehyde or ketone (8 eq) in methanol is heated at reflux for 2-6 h. After cooling to 0 'C sodium 15 cyanoborohydride (2-3 eq) is added. The reaction mixture is stirred for 3-16 h at room temperature and quenched with 1 M aqueous sodium hydroxide solution. The aqueous layer is extracted with ethyl acetate. The combined organic layers are dried over anhydrous sodium sulfate and concentrated in vacuo. Flash chromatography gives an N-alkyl derivative of formula (I). 20 Example 1 trans-8-Chloro-l-(4-phenoxy-cyclohexyl)-4H,6H-2,3,5,10b-tetraaza-benzoazulene-5 carboxylic acid tert-butyl ester The title compound was obtained as white foam in 83% yield according to general procedure V. Hydrazide: trans-4-Phenoxy-cyclohexanecarboxylic acid hydrazide 25 Thiolactam: 7-Chloro-2-thioxo- 1,2,3,5-tetrahydro-benzo[e] [ 1,4]diazepine-4-carboxylic acid tert butyl ester MS m/e: 495 (M+H) Example 2 trans-8-Chloro-1-(4-phenoxy-cyclohexyl)-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene 30 hydrochloride The title compound was obtained as white solid in 98% yield from trans-8-chloro- 1 -(4-phenoxy cyclohexyl)-4H,6H-2,3,5,10b-tetraaza-benzoazulene-5-carboxylic acid tert-butyl ester according to general procedure VI. MS m/e: 395 (M+H) Example 3 WO 2010/060836 PCT/EP2009/065354 - 62 trans-8-Chloro-5-methyl- 1 -(4-phenoxy-cyclohexyl)-5,6-dihydro-4H-2,3,5,1 Ob-tetraaza benzo[e]azulene The title compound was obtained as white solid in 64% yield from trans-8-chloro-1-(4-phenoxy cyclohexyl)-5,6-dihydro-4H-2,3,5, 10b-tetraaza-benzoazulene hydrochloride and 5 paraformaldehyde according to general procedure VII. MS m/e: 409 (M+H). Example 4 trans-I- [8-Chloro- 1-(4-phenoxy-cyclohexyl)-4H,6H-2,3,5, Ob-tetraaza-benzoazuen-5-yl] ethanone To a solution of trans-8-chloro-1-(4-phenoxy-cyclohexyl)-5,6-dihydro-4H-2,3,5,10b-tetraaza 10 benzoazulene hydrochloride (0.071 g, 0.18 mmol) and triethylamine (0.048 ml, 0.35 nunol) in dichloromethane was added acetyl chloride (0.013 ml, 0.18 mmol) at room temperature. Stirring for 18 h was followed by partitioning between 1 M aqueous sodium hydroxide solution (50 ml) and dichloromethane (50 ml). The organic layer was separated. The aqueous layer was extracted with one 50-ml portion of dichloromethane. The combined organic layers were dried over 15 anhydrous sodium sulfate and concentrated in vacuo. Purification by flash-chromatography with n-heptane/ethyl acetate as eluent gave the title compound (0.039 g, 54%) as white solid. MS m/e: 437 (M+HV). Example 5 trans-8-Chloro-5-methanesulfonyl-1-(4-phenoxy-cyclohexyl)-5,6-dihydro-4H-2,3,5,10b 20 tetraaza-benzoazulene To a solution of trans-8-chloro-1-(4-phenoxy-cyclohexyl)-5,6-dihydro-4H-2,3,5,10b-tetraaza benzoazulene hydrochloride (0.065 g, 0.15 mmol) and triethylamine (0.044 ml, 0.32 mmol) in dichloromethane (5 ml) was added methanesulfonyl chloride (0.013 ml, 0.17 mmol) at room temperature. After stirring for 20 h the reaction mixture was transferred directly onto a silica gel 25 chromatography column. Elution with n-heptane/ethyl acetate gave the title compound (0.051 g, 72%) as white solid. MS m/e: 473 (M+H*). Example 6 trans-2-[8-Chloro-1-(4-phenoxy-eyclohexyl)-4H,6H-2,3,5,10b-tetraaza-benzoazulen-5-yll ethanol 30 The title compound was obtained as white solid in 59% yield from trans-8-chloro-1-(4-phenoxy cyclohexyl)-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene hydrochloride and glycolaldehyde according to general procedure VII. MS m/e: 439 (M+H). Example 7 WO 2010/060836 PCT/EP2009/065354 - 63 trans-8-Chloro-5-isopropyl- 1-(4-phenoxy-cyclohexyl)-5,6-dihydro-4H-2,3,5,1 Ob-tetraaza benzoazulene The title compound was obtained as white solid in 45% yield from trans-8-chloro-1-(4-phenoxy cyclohexyl)-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene hydrochloride and acetone 5 according to general procedure VII. MS m/e: 437 (M+H). Example 8 trans-8-Chloro-1-(4-phenoxy-cyclohexyl)-4H,6H-2,3,5,10b-tetraaza-benzoazulene-5 sulfonic acid dimethylamide To a solution of trans-8-chloro-1-(4-phenoxy-cyclohexyl)-5,6-dihydro-4H-2,3,5,10b-tetraaza 10 benzoazulene hydrochloride (0.062 g, 0.14 mmol) and triethylamine (0.030 ml, 0.22 nunol) in dichloromethane (2.5 ml) was added N,N-dimethylsulfainoyl chloride (0.023 ml, 0.22 mmol) at room temperature. After stirring for 72 h the reaction mixture was transferred directly onto a silica gel chromatography column. Elution with n-heptane/ethyl acetate gave the title compound (0.042 g, 58%) as white solid. MS m/e: 502 (M+H). 15 Example 9 trans-8-Chloro-1-(4-phenoxy-cyclohexyl)-5-pyridin-2-ylmethyl-5,6-dihydro-4H-2,3,5,10b tetraaza-benzoazulene To a mixture of trans-8-chloro- 1 -(4-phenoxy-cyclohexyl)-5,6-dihydro-4H-2,3,5, 1 Ob-tetraaza benzoazulene hydrochloride (0.064 g, 0.15 nmol) and potassium carbonate (0.062 ml, 0.45 20 mmol) in acetonitrile (1 ml) was added 2-(bromomethyl)pyridine hydrobromide (0.040 ml, 0.16 mmol) at room temperature. Stirring for 72 h at 50 'C was followed by partitioning between 1 M aqueous sodium hydroxide solution (50 ml) and dichloromethane (50 ml). The organic layer was separated. The aqueous layer was extracted with two 50-ml portions of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. 25 Purification by flash-chromatography with n-heptane/ethyl acetate as eluent gave the title compound (0.044 g, 63%) as light brown solid. MS m/e: 486 (M+H). Example 10 trans-I- [8-Chloro-1-(4-phenoxy-cyclohexyl)-4H,6H-2,3,5, 1Ob-tetraaza-benzoazulen-5-yll -2 dimethylamino-ethanone 30 To a mixture of trans-8-chloro- 1 -(4-phenoxy-cyclohexyl)-5,6-dihydro-4H-2,3,5, 1 Ob-tetraaza benzoazulene hydrochloride (0.179 g, 0.41 mmol) in tetrahydrofuran (2 ml) was added triethylamine (0.058 ml, 0.41 mmol). The suspension was stirred for 10 minutes. The ammonium salts were removed by filtration. The filtrate was concentrated in vacuo. The residue was redissolved in tetrahydrofuran (3 ml) followed by consecutive addition of N,N-dimethylglycine WO 2010/060836 PCT/EP2009/065354 - 64 (0.056 g, 0.54 mmol) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.104 g, 0.54 mmol. Stirring for 18 h at 50 'C was followed by partitioning between water (50 ml) and dichloromethane (50 ml). The organic layer was separated. The aqueous layer was extracted with one 50-ml portion of dichloromethane. The combined organic layers were dried 5 over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash-chromatography with n-heptane/ethyl acetate as eluent gave the title compound (0.057 g, 28%) as white solid. MS m/e: 480 (M+H+). Example 11 trans-8-Fluoro-1-(4-phenoxy-cyclohexyl)-4H,6H-2,3,5,10b-tetraaza-benzo[e]azulene-5 10 carboxylic acid tert-butyl ester The title compound was obtained as white solid in 54% yield according to general procedure V. Hydrazide: trans-4-Phenoxy-cyclohexanecarboxylic acid hydrazide Thiolactam: 7-Fluoro-2-thioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepine-4-carboxylic acid tert butyl ester 15 MS m/e: 479 (M+H ) Example 12 trans-8-Fluoro-1-(4-phenoxy-cyclohexyl)-5,6-dihydro-4H-2,3,5,10b-tetraaza benzo[e]azulene hydrochloride The title compound was obtained as light yellow solid in quantitative yield from trans-8-fluoro 20 1-(4-phenoxy-cyclohexyl)-4H,6H-2,3,5, 1 Ob-tetraaza-benzoazulene-5-carboxylic acid tert-butyl ester according to general procedure VI. MS m/e: 379 (M+H) Example 13 trans-8-Fluoro-5-methyl-1-(4-phenoxy-cyclohexyl)-5,6-dihydro-4H-2,3,5,10b-tetraaza benzoazulene 25 The title compound was obtained as white solid in 63% yield from trans-8-fluoro-1-(4-phenoxy cyclohexyl)-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene hydrochloride and paraformaldehyde according to general procedure VII. MS m/e: 393 (M+H). Example 14 cis-8-Chloro-1-(4-phenoxy-cyclohexyl)-4H,6H-2,3,5,10b-tetraaza-benzoazulene-5 30 carboxylic acid tert-butyl ester The title compound was obtained as white solid in 69% yield according to general procedure V. Hydrazide: cis-4-Phenoxy-cyclohexanecarboxylic acid hydrazide Thiolactam: 7-Chloro-2-thioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepine-4-carboxylic acid tert butyl ester WO 2010/060836 PCT/EP2009/065354 - 65 MS m/e: 495 (M+H') Example 15 cis-8-Chloro-1-(4-phenoxy-cyclohexyl)-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene hydrochloride 5 The title compound was obtained as white solid in quantitative yield from cis-8-chloro-1-(4 phenoxy-cyclohexyl)-4H,6H-2,3,5,10b-tetraaza-benzoazu lene-5-carboxylic acid tert-butyl ester according to general procedure VI. MS m/e: 395 (M+H) Example 16 cis-8-Chloro-5-methyl-1-(4-phenoxy-cyclohexyl)-5,6-dihydro-4H-2,3,5,10b-tetraaza 10 benzoazulene The title compound was obtained as white solid in 73% yield from cis-8-chloro-l-(4-phenoxy cyclohexyl)-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene hydrochloride and paraformaldehyde according to general procedure VII. MS m/e: 409 (M+H) Example 17 15 trans-8-Chloro-1-[4-(4-fluoro-phenoxy)-cyclohexyl]-4H,6H-2,3,5,10b-tetraaza benzoazulene-5-carboxylic acid tert-butyl ester The title compound was obtained as white solid in 66% yield according to general procedure V. Hydrazide: trans-4-(4-Fluoro-phenoxy)-cyclohexanecarboxylic acid hydrazide Thiolactam: 7-Chloro-2-thioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepine-4-carboxylic acid tert 20 butyl ester MS m/e: 513 (M1\+H) Example 18 trans-8-Chloro-1-[4-(4-fluoro-phenoxy)-cyclohexyll-5,6-dihydro-4H-2,3,5,10b-tetraaza benzo[elazulene hydrochloride 25 The title compound was obtained as white solid in quantitative yield from trans-8-chloro-1-[4-(4 fluoro-phenoxy)-cyclohexyl]-4H,6H-2,3,5, 1 Ob-tetraaza-benzoazulene-5-carboxylic acid tert butyl ester according to general procedure VI. MS m/e: 413 (M+H) Example 19 trans-8-Chloro-1-[4-(4-fluoro-phenoxy)-cyclohexyl]-5-methyl-5,6-dihydro-4H-2,3,5,10b 30 tetraaza-benzoazulene The title compound was obtained as white solid in 70% yield from trans-8-chloro-1-[4-(4-fluoro phenoxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene hydrochloride and paraformaldehyde according to general procedure VII. MS m/e: 427 (M+H) Example 20 WO 2010/060836 PCT/EP2009/065354 - 66 trans-8-Chloro-1 -[4-(4-cyano-phenoxy)-cyclohexyl]-4H,6H-2,3,5,1 Ob-tetraaza benzo[e]azulene-5-carboxylic acid tert-butyl ester The title compound was obtained according to general procedure V. Hydrazide: trans-4-(4-Cyano-phenoxy)-cyclohexanecarboxylic acid hydrazide 5 Thiolactam: 7-Chloro-2-thioxo-1,2,3,5-tetrahydro-benzo[e][1 ,4]diazepine-4-carboxylic acid tert butyl ester. MS m/e: 520 (M+-HF) Example 21 trans-4-[4-(8-Chloro-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulen-1-yl) 10 cyclohexyloxy]-benzonitrile hydrochloride The title compound was obtained from trans-8-chloro-1-[4-(4-cyano-phenoxy)-cyclohexyl] 4H,6H-2,3,5,10b-tetraaza-benzo[e]azulene-5-carboxylic acid tert-butyl ester according to general procedure VI. MS m/e: 420 (M+H) Example 22 15 trans-4-[4-(8-Chloro-5-methyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulen-1-yl) cyclohexyloxy]-benzonitrile The title compound was obtained from trans-4-[4-(8-chloro-5,6-dihydro-4H-2,3,5, 10b-tetraaza benzo[e]azulen-1-yl)-cyclohexyloxy]-benzonitrile hydrochloride and paraformaldehyde according to general procedure VII. MS m/e: 434 (M+H) 20 Example 23 trans-8-Chloro-1-[4-(4-trifluoromethyl-phenoxy)-cyclohexyl]-4H,6H-2,3,5,10b-tetraaza benzo[elazulene-5-carboxylic acid tert-butyl ester The title compound was obtained according to general procedure V. Hydrazide: trans-4-(4-Trifluoromethyl-phenoxy)-cyclohexanecarboxylic acid hydrazide 25 Thiolactam: 7-Chloro-2-thioxo- 1,2,3,5-tetrahydro-benzo[e] [ 1,4]diazepine-4-carboxylic acid tert butyl ester MS m/e: 563 (M+H) Example 24 trans-8-Chloro-1-[4-(4-trifluoromethyl-phenoxy)-cyclohexyl-5,6-dihydro-4H-2,3,5,10b 30 tetraaza-benzo[elazulene hydrochloride The title compound was obtained from trans-8-chloro-1-[4-(4-trifluoromethyl-phenoxy) cyclohexyl]-4H,6H-2,3,5,10b-tetraaza-benzo[e]azulene-5-carboxylic acid tert-butyl ester according to general procedure VI. MS m/e: 463 (M+H) Example 25 WO 2010/060836 PCT/EP2009/065354 - 67 trans-8-Chloro-5-methyl-1 - [4-(4-trifluoromethyl-phenoxy)-cyclohexyl] -5,6-dihydro-4H 2,3,5,1 Ob-tetraaza-benzo[e]azulene The title compound was obtained from trans-8-chloro-I -[4-(4-trifluoromethyl-phenoxy) cyclohexyl]-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene hydrochloride and 5 paraformaldehyde according to general procedure VII. MS n/e: 477 (M+H) Example 26 trans-8-Chloro-1-[4-(3-chloro-phenoxy)-cyclohexyll-4H,6H-2,3,5,10b-tetraaza benzoazulene-5-carboxylic acid tert-butyl ester The title compound was obtained as white solid in 74% yield according to general procedure V. 10 Hydrazide: trans-4-(3-Chloro-phenoxy)-cyclohexanecarboxylic acid hydrazide Thiolactam: 7-Chloro-2-thioxo- 1,2,3,5-tetrahydro-benzo[e] [1,4]diazepine-4-carboxylic acid tert butyl ester MS m/e: 529 (M+HV) Example 27 15 trans-8-Chloro-1-[4-(3-chloro-phenoxy)-cyclohexyll-5,6-dihydro-4H-2,3,5,10b-tetraaza benzoazulene hydrochloride The title compound was obtained in quantitative yield from trans-8-chloro-1-[4-(3-chloro phenoxy)-cyclohexyl]-4H,6H-2,3,5,10b-tetraaza-benzoazulene-5-carboxylic acid tert-butyl ester according to general procedure VI. MS m/e: 429 (M+H) 20 Example 28 trans-8-Chloro-1-[4-(3-chloro-phenoxy)-cyclohexyl]-5-methyl-5,6-dihydro-4H-2,3,5,10b tetraaza-benzoazulene The title compound was obtained as colorless oil in 83% yield from trans-8-chloro-1-[4-(3 chloro-phenoxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene hydrochloride 25 and paraformaldehyde according to general procedure VII. MS m/e: 443 (M+H) Example 29 trans-8-Chloro-l-[4-(3-methoxy-phenoxy)-cyclohexyll-4H,6H-2,3,5,10b-tetraaza benzoazulene-5-carboxylic acid tert-butyl ester The title compound was obtained as white foam in 75% yield according to general procedure V. 30 Hydrazide: trans-4-(3-Methoxy-phenoxy)-cyclohexanecarboxylic acid hydrazide Thiolactam: 7-Chloro-2-thioxo- 1,2,3,5-tetrahydro-benzo[e] [ 1,4]diazepine-4-carboxylic acid tert butyl ester MS m/e: 525.5 (M+H) Example 30 WO 2010/060836 PCT/EP2009/065354 - 68 trans-8-Chloro- 1- [4-(3-methoxy-phenoxy)-cyclohexyl] -5,6-dihydro-4H-2,3,5, 1 Ob-tetraaza benzo[e]azulene hydrochloride The title compound was obtained as white solid in quantitative yield from trans-8-chloro-1-[4-(3 methoxy-phenoxy)-cyclohexyl]-4H,6H-2,3,5, I Ob-tetraaza-benzoazulene-5-carboxylic acid tert 5 butyl ester according to general procedure VI. MS m/e: 425 (M+rHv) Example 31 trans-8-Chloro-1-[4-(3-methoxy-phenoxy)-cyclohexyl]-5-methyl-5,6-dihydro-4H-2,3,5,10b tetraaza-benzoazulene The title compound was obtained as white solid in 43% yield from trans-8-chloro-1-[4-(3 10 methoxy-phenoxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene hydrochloride and paraformaldehyde according to general procedure VII. MS m/e: 439 (M+H) Example 32 trans-8-Chloro-1-[4-(3-cyano-phenoxy)-cyclohexyl]-4H,6H-2,3,5,10b-tetraaza benzoazulene-5-carboxylic acid tert-butyl ester 15 The title compound was obtained as brown solid in 18% yield with a purity of approximately 80% by LC-MS according to general procedure V. Hydrazide trans-4-(3-Cyano-phenoxy)-cyclohexanecarboxylic acid hydrazide Thiolactam: 7-Chloro-2-thioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepine-4-carboxylic acid tert butyl ester 20 MS m/e: 520 (M+H ) Example 33 trans-3-[4-(8-Chloro-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulen-1-yl)-cvclohexyloxy] benzonitrile hydrochloride The title compound was obtained as brown solid in 95% yield from trans-8-chloro-1-[4-(3 25 cyano-phenoxy)-cyclohexyl]-4H,6H-2,3,5, 10b-tetraaza-benzoazulene-5-carboxylic acid tert butyl ester according to general procedure VI. MS m/e: 420 (M+H--) Example 34 trans-3-[4-(8-Chloro-5-methyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulen-1-yl) cyclohexyloxyl-benzonitrile 30 The title compound was obtained as yellow solid in 43% yield from trans-3-[4-(8-chloro-5,6 dihydro-4H-2,3,5,10b-tetraaza-benzoazulen-1-yl)-cyclohexyloxy]-benzonitrile hydrochloride and paraformaldehyde according to general procedure VII. MS m/e: 434 (M+H) Example 35 WO 2010/060836 PCT/EP2009/065354 - 69 trans-8-Chloro-1-(4-m-tolyloxy-cyclohexyl)-4H,6H-2,3,5,1 Ob-tetraaza-benzo [e] azulene-5 carboxylic acid tert-butyl ester The title compound was obtained according to general procedure V. Hydrazide: trans-4-m-Tolyloxy-cyclohexanecarboxylic acid hydrazide 5 Thiolactam: 7-Chloro-2-thioxo-1,2,3,5-tetrahydro-benzo[e][1 ,4]diazepine-4-carboxylic acid tert butyl ester MS m/e: 509 (M+H-) Example 36 trans-8-Chloro-1-(4-m-tolyloxy-cyclohexyl)-5,6-dihydro-4H-2,3,5,10b-tetraaza 10 benzo[e]azulene hydrochloride The title compound was obtained trans-8-chloro- 1-(4-m-tolyloxy-cyclohexyl)-4H,6H-2,3 ,5, 1Ob tetraaza-benzo[e]azulene-5-carboxylic acid tert-butyl ester according to general procedure VI. MS m/e: 409 (M+HV) Example 37 15 trans-8-Chloro-5-methyl-1-(4-m-tolyloxy-cyclohexyl)-5,6-dihydro-4H-2,3,5,10b-tetraaza benzo[e]azulene The title compound was obtained from trans-8-chloro-1-(4-m-tolyloxy-cyclohexyl)-5,6-dihydro 4H-2,3,5, 1 Ob-tetraaza-benzo [e] azulene hydrochloride and paraformaldehyde according to general procedure VII. MS m/e: 423.5 (M+H) 20 Example 38 trans-I- [4-(3-tert-Butyl-phenoxy)-cyclohexyl] -8-chloro-4H,6H-2,3,5,1 Ob-tetraaza benzo[elazulene-5-carboxylic acid tert-butyl ester The title compound was obtained according to general procedure V. Hydrazide: trans-4-(3-tert-Butyl-phenoxy)-cyclohexanecarboxylic acid hydrazide 25 Thiolactam: 7-Chloro-2-thioxo- 1,2,3,5-tetrahydro-benzo[e] [ 1,4]diazepine-4-carboxylic acid tert butyl ester. MS m/e: 551.5 (M+H) Example 39 trans-I- [4-(3-tert-Butyl-phenoxy)-cyclohexyl] -8-chloro-5,6-dihydro-4H-2,3,5, Ob-tetraaza benzo[elazulene hydrochloride 30 The title compound was obtained trans-I -[4-(3-tert-butyl-phenoxy)-cyclohexyl]-8-chloro 4H,6H-2,3,5,10b-tetraaza-benzo[e]azulene-5-carboxylic acid tert-butyl ester according to general procedure VI. MS m/e: 451 (M+H) Example 40 WO 2010/060836 PCT/EP2009/065354 - 70 trans-I- [4-(3-tert-Butyl-phenoxy)-cyclohexyl]-8-chloro-5-methyl-5,6-dihydro-4H-2,3,5,1Ob tetraaza-benzo[e]azulene The title compound was obtained from trans-1-[4-(3-tert-butyl-phenoxy)-cyclohexyl]-8-chloro 5,6-dihydro-4H-2,3,5, 1Ob-tetraaza-benzo[e]azulene hydrochloride and paraformaldehyde 5 according to general procedure VII. MS m/e: 465 (M+H) Example 41 trans-8-Chloro-1-[4-(3-trifluoromethyl-phenoxy)-cyclohexyl]-4H,6H-2,3,5,10b-tetraaza benzo[e]azulene-5-carboxylic acid tert-butyl ester The title compound was obtained according to general procedure V. 10 Hydrazide: trans-4-(3-Trifluoromethyl-phenoxy)-cyclohexanecarboxylic acid hydrazide Thiolactam: 7-Chloro-2-thioxo- 1,2,3,5-tetrahydro-benzo[e] [1,4]diazepine-4-carboxylic acid tert butyl ester MS m/e: 563 (M+HV) Example 42 15 trans-8-Chloro-1-[4-(3-trifluoromethyl-phenoxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b tetraaza-benzo[elazulene hydrochloride The title compound was obtained from trans-8-chloro-1-[4-(3-trifluoromethyl-phenoxy) cyclohexyl]-4H,6H-2,3,5,10b-tetraaza-benzo[e]azulene-5-carboxylic acid tert-butyl ester according to general procedure VI. MS m/e: 463 (M+H) 20 Example 43 trans-8-Chloro-1-[4-(2-fluoro-phenoxy)-cyclohexyl]-4H,6H-2,3,5,10b-tetraaza benzo[elazulene-5-carboxylic acid tert-butyl ester The title compound was obtained according to general procedure V. Hydrazide: trans-4-(2-Fluoro-phenoxy)-cyclohexanecarboxylic acid hydrazide 25 Thiolactam: 7-Chloro-2-thioxo- 1,2,3,5-tetrahydro-benzo[e] [ 1,4]diazepine-4-carboxylic acid tert butyl ester MS m/e: 513 (M+H*) Example 44 trans-8-Chloro-1-[4-(2-fluoro-phenoxy)-cyclohexyll-5,6-dihydro-4H-2,3,5,10b-tetraaza 30 benzo[elazulene hydrochloride The title compound was obtained from trans-8-chloro-1-[4-(2-fluoro-phenoxy)-cyclohexyl] 4H,6H-2,3,5,10b-tetraaza-benzo[e]azulene-5-carboxylic acid tert-butyl ester according to general procedure VI. MS m/e: 413 (M+H) Example 45 WO 2010/060836 PCT/EP2009/065354 - 71 trans-8-Chloro-1-[4-(2-fluoro-phenoxy)-cyclohexyl]-5-methyl-5,6-dihydro-4H-2,3,5,1 Ob tetraaza-benzo [e] azulene The title compound was obtained from trans-8-chloro- I -[4-(2-fluoro-phenoxy)-cyclohexyl]-5,6 dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene hydrochloride and paraformaldehyde according 5 to general procedure VII. MS m/e: 427.5 (M+H) Example 46 trans-8-Chloro-1-[4-(2-cyano-phenoxy)-cyclohexyl]-4H,6H-2,3,5,10b-tetraaza benzoazulene-5-carboxylic acid tert-butyl ester The title compound was obtained as white foam in 52% yield according to general procedure V. 10 Hydrazide: trans-4-(2-Cyano-phenoxy)-cyclohexanecarboxylic acid hydrazide Thiolactam: 7-Chloro-2-thioxo- 1,2,3,5-tetrahydro-benzo[e] [1,4]diazepine-4-carboxylic acid tert butyl ester MS m/e: 520 (M+HV) Example 47 15 trans-2-[4-(8-Chloro-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulen-l-yl) cyclohexyloxy]-benzonitrile hydrochloride The title compound was obtained as white solid in 99% yield from trans-8-chloro-1-[4-(2-cyano phenoxy)-cyclohexyl]-4H,6H-2,3,5,10b-tetraaza-benzoazulene-5-carboxylic acid tert-butyl ester according to general procedure VI. MS m/e: 420 (M+H) 20 Example 48 trans-2-[4-(8-Chloro-5-methyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulen-1-yl) cyclohexyloxyl-benzonitrile The title compound was obtained as white solid in 50% yield from trans-2-[4-(8-chloro-5,6 dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulen-1-yl)-cyclohexyloxy]-benzonitrile hydrochloride 25 and paraformaldehyde according to general procedure VII. MS m/e: 434 (M+H) Example 49 trans-8-Chloro-1-(4-o-tolyloxy-cyclohexyl)-4H,6H-2,3,5,10b-tetraaza-benzoazulene-5 carboxylic acid tert-butyl ester The title compound was obtained as yellow solid in 52% yield according to general procedure V. 30 Hydrazide: trans-4-o-Tolyloxy-cyclohexanecarboxylic acid hydrazide Thiolactam: 7-Chloro-2-thioxo- 1,2,3,5-tetrahydro-benzo[e] [ 1,4]diazepine-4-carboxylic acid tert butyl ester MS m/e: 509 (M+H) Example 50 WO 2010/060836 PCT/EP2009/065354 - 72 trans-8-Chloro- 1 -(4-o-tolvloxy-cyclohexyl)-5,6-dihydro-4H-2,3,5,1 Ob-tetraaza benzoazulene hydrochloride The title compound was obtained as light yellow solid in quantitative yield from trans-8-chloro 1-(4-o-tolyloxy-cyclohexyl)-4H,6H-2,3,5,1 Ob-tetraaza-benzoazulene-5-carboxylic acid tert-butyl 5 ester according to general procedure VI. MS m/e: 409 (M+H) Example 51 trans-8-Chloro-5-methyl-1-(4-o-tolyloxy-cvclohexyl)-5,6-dihydro-4H-2,3,5,10b-tetraaza benzoazulene The title compound was obtained as light yellow solid in 72% yield from trans-8-chloro-1-(4-o 10 tolyloxy-cyclohexyl)-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene hydrochloride and paraformaldehyde according to general procedure VII. MS m/e: 423 (M+H) Example 52 trans-8-Chloro-1-[4-(3,5-difluoro-phenoxy)-cyclohexyl]-4H,6H-2,3,5,1Ob-tetraaza benzoazulene-5-carboxylic acid tert-butyl ester 15 The title compound was obtained as light yellow solid in 58% yield according to general procedure V. Hydrazide: trans-4-(3,5-Difluoro-phenoxy)-cyclohexanecarboxylic acid hydrazide Thiolactam: 7-Chloro-2-thioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepine-4-carboxylic acid tert butyl ester 20 Example 53 trans-8-Chloro-1-[4-(3,5-difluoro-phenoxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b-tetraaza benzoazulene hydrochloride The title compound was obtained as white solid in quantitative yield from trans-8-chloro-1-[4 (3,5-difluoro-phenoxy)-cyclohexyl]-4H,6H-2,3,5,10b-tetraaza-benzoazulene-5-carboxylic acid 25 tert-butyl ester according to general procedure VI. MS m/e: 431 (M+H) Example 54 trans-8-Chloro-1-[4-(3,5-difluoro-phenoxy)-cyclohexyll-5-methyl-5,6-dihydro-4H-2,3,5,10b tetraaza-benzoazulene The title compound was obtained as white solid in 39% yield from trans-8-chloro-1-[4-(3,5 30 difluoro-phenoxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene hydrochloride and paraformaldehyde according to general procedure VII. MS m/e: 445 (M+H) Example 55 trans-8-Chloro-1-[4-(naphthalen-2-yoxy)-cyclohexyl]-4H,6H-2,3,5,10b-tetraaza benzoazulene-5-carboxylic acid tert-butyl ester WO 2010/060836 PCT/EP2009/065354 - 73 The title compound was obtained as yellow solid in 78% yield according to general procedure V. Hydrazide: trans-4-(Naphthalen-2-yloxy)-cyclohexanecarboxylic acid hydrazide Thiolactam: 7-Chloro-2-thioxo- 1,2,3,5-tetrahydro-benzo[e] [1,4]diazepine-4-carboxylic acid tert butyl ester 5 MS m/e: 545 (M-H) Example 56 trans-8-Chloro-1-[4-(naphthalen-2-vloxy)-cvclohexyl]-5,6-dihydro-4H-2,3,5,10b-tetraaza benzoazulene hydrochloride The title compound was obtained as white solid in quantitative yield from trans-8-chloro-1-[4 10 (naphthalen-2-yloxy)-cyclohexyl]-4H,6H-2,3,5,10b-tetraaza-benzoazulene-5-carboxylic acid tert-butyl ester according to general procedure VI. MS m/e: 445 (M+H) Example 57 trans-8-Chloro-5-methyl-1-[4-(naphthalen-2-yloxy)-cyclohexyl-5,6-dihydro-4H-2,3,5,10b tetraaza-benzoazulene 15 The title compound was obtained as white foam in 60% yield from trans-8-chloro-1-[4 (naphthalen-2-yloxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene hydrochloride and paraformaldehyde according to general procedure VII. MS m/e: 459 (M+H+) Example 58 trans-8-Chloro-1-[4-(naphthalen-1-yloxy)-cyclohexyl]-4H,6H-2,3,5,10b-tetraaza 20 benzoazulene-5-carboxylic acid tert-butyl ester The title compound was obtained as yellow solid in 73% yield according to general procedure V. Hydrazide: trans-4-(Naphthalen-1-yloxy)-cyclohexanecarboxylic acid hydrazide Thiolactam: 7-Chloro-2-thioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepine-4-carboxylic acid tert butyl ester 25 MS m/e: 545 (M+Hv) Example 59 trans-8-Chloro-1-[4-(naphthalen-1-yloxy)-cyclohexyl-5,6-dihydro-4H-2,3,5,10b-tetraaza benzoazulene The title compound was obtained as white solid in 97% yield from trans-8-chloro-1-[4 30 (naphthalen-1-yloxy)-cyclohexyl]-4H,6H-2,3,5,10b-tetraaza-benzoazulene-5-carboxylic acid tert-butyl ester according to general procedure VI. MS m/e: 445 (M+H) Example 60 trans-8-Chloro-5-methyl-1-[4-(naphthalen-1-yloxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b tetraaza-benzoazulene WO 2010/060836 PCT/EP2009/065354 - 74 The title compound was obtained as white foam in 73% yield from trans-8-chloro-1-[4 (naphthalen- 1 -yloxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5,1 Ob-tetraaza-benzoazulene hydrochloride and paraformaldehyde according to general procedure VII. MS m/e: 459 (M+H) Example 61 5 trans-8-Chloro-1-[4-(pyridin-3-yloxy)-cyclohexyl]-4H,6H-2,3,5,10b-tetraaza-benzoazulene 5-carboxylic acid tert-butyl ester The title compound was obtained as white foam in 510% yield according to general procedure V. Hydrazide: trans-4-(Pyridin-3-yloxy)-cyclohexanecarboxylic acid hydrazide Thiolactam: 7-Chloro-2-thioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepine-4-carboxylic acid tert 10 butyl ester. MS m/e: 496 (M+H) Example 62 trans-8-Chloro-1-[4-(pyridin-3-yoxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b-tetraaza benzo[e]azulene dihydrochloride The title compound was obtained as white solid in quantitative yield from trans-8-chloro-1-[4 15 (pyridin-3-yloxy)-cyclohexyl]-4H,6H-2,3,5, 1Ob-tetraaza-benzoazulene-5-carboxylic acid tert butyl ester according to general procedure VI. MS m/e: 396 (M+Hv) Example 63 trans-8-Chloro-5-methyl-1-[4-(pyridin-3-yloxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b tetraaza-benzoazulene 20 The title compound was obtained as white solid in 41% yield from trans-8-chloro-1-[4-(pyridin 3-yloxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene dihydrochloride and paraformaldehyde according to general procedure VII. MS m/e: 410 (M+H ) Example 64 trans-8-Chloro-1-[4-(5-chloro-pyridin-3-yloxy)-cyclohexyll-4H,6H-2,3,5,10b-tetraaza 25 benzoazulene-5-carboxylic acid tert-butyl ester The title compound was obtained as white foam in 710% yield according to general procedure V. Hydrazide: trans-4-(5-Chloro-pyridin-3-yloxy)-cyclohexanecarboxylic acid hydrazide Thiolactam: 7-Chloro-2-thioxo- 1,2,3,5-tetrahydro-benzo[e]l 1,4]diazepine-4-carboxylic acid tert butyl ester. MS m/e: 530 (M+H) 30 Example 65 trans-8-Chloro-l-[4-(5-chloro-pyridin-3-yloxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b tetraaza-benzoazulene hydrochloride WO 2010/060836 PCT/EP2009/065354 - 75 The title compound was obtained as white solid in quantitative yield from trans-8-chloro-1-[4-(5 chloro-pyridin-3-yloxy)-cyclohexyl]-4H,6H-2,3,5,10b-tetraaza-benzoazulene-5-carboxylic acid tert-butyl ester according to general procedure VI. MS m/e: 430 (M+H) Example 66 5 trans-8-Chloro-l-[4-(5-chloro-pyridin-3-vloxy)-cyclohexyl]-5-methyl-5,6-dihydro-4H 2,3,5,10b-tetraaza-benzoazulene The title compound was obtained as white solid in 65% yield from trans-8-chloro-I-[4-(5-chloro pyridin-3-yloxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene hydrochloride and paraformaldehyde according to general procedure VI. MS m/e: 444 (M+H) 10 Example 67 trans-8-Chloro-1-[4-(pyridin-2-yloxy)-cyclohexyl]-4H,6H-2,3,5,10b-tetraaza-benzoazulene 5-carboxylic acid tert-butyl ester The title compound was obtained as white foam in 77% yield according to general procedure V. Hydrazide: trans-4-(Pyridin-2-yloxy)-cyclohexanecarboxylic acid hydrazide 15 Thiolactam: 7-Chloro-2-thioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepine-4-carboxylic acid tert butyl ester. MS m/e: 496 (M+H) Example 68 trans-8-Chloro-1-[4-(pyridin-2-yoxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b-tetraaza benzoazulene hydrochloride 20 The title compound was obtained as white solid in quantitative yield from trans-8-chloro-1-[4 (pyridin-2-yloxy)-cyclohexyl]-4H,6H-2,3,5, 1Ob-tetraaza-benzoazulene-5-carboxylic acid tert butyl ester according to general procedure VI. MS m/e: 396 (M+H+) Example 69 trans-8-Chloro-5-methyl-1-[4-(pyridin-2-yloxy)-cyclohexyll-5,6-dihydro-4H-2,3,5,10b 25 tetraaza-benzoazulene The title compound was obtained as white solid in 41% yield from trans-8-chloro-1-[4-(pyridin 2-yloxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene hydrochloride and paraformaldehyde according to general procedure VII. MS m/e: 410 (M+H) Example 70 30 trans-8-Chloro-1-[4-(6-chloro-pyridin-2-yloxy)-cyclohexyll-4H,6H-2,3,5,1Ob-tetraaza benzo[e]azulene-5-carboxylic acid tert-butyl ester The title compound was obtained according to general procedure V. Hydrazide: trans-4-(6-Chloro-pyridin-2-yloxy)-cyclohexanecarboxylic acid hydrazide WO 2010/060836 PCT/EP2009/065354 - 76 Thiolactam: 7-Chloro-2-thioxo-1,2,3,5-tetrahydro-benzo[e] [1,4]diazepine-4-carboxylic acid tert butyl ester. MS m/e: 530 (M+H ) Example 71 trans-8-Chloro-1-[4-(6-chloro-pyridin-2-yoxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b 5 tetraaza-benzo[elazulene hydrochloride The title compound was from trans-8-chloro- 1- [4-(6-ch loro-pyrid in-2-yloxy)-cyclohexyl] 4H,6H-2,3,5,1 Ob-tetraaza-benzo [e]azulene-5-carboxyl ic acid tert-butyl ester according to general procedure VI. MS m/e: 430 (M+H) Example 72 10 trans-8-Chloro-l-[4-(6-chloro-pyridin-2-yloxy)-cyclohexyl]-5-methyl-5,6-dihydro-4H 2,3,5,10b-tetraaza-benzo[e]azulene The title compound was obtained from trans-8-chloro- 1 -[4-(6-chloro-pyridin-2-yloxy) cyclohexyl]-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene hydrochloride and paraformaldehyde according to general procedure VII. MS m/e: 444 (M+H) 15 Example 73 trans-8-Chloro-1-[4-(5-chloro-pyridin-2-yloxy)-cyclohexyl]-4H,6H-2,3,5,10b-tetraaza benzo[e]azulene-5-carboxylic acid tert-butyl ester The title compound was obtained according to general procedure V. Hydrazide: trans-4-(5-Chloro-pyridin-2-yloxy)-cyclohexanecarboxylic acid hydrazide 20 Thiolactam: 7-Chloro-2-thioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepine-4-carboxylic acid tert butyl ester MS m/e: 530 (M+H) Example 74 trans-8-Chloro-l-[4-(5-chloro-pyridin-2-yloxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b tetraaza-benzo[eJazulene hydrochloride 25 The title compound was obtained from trans-8-chloro-1-[4-(5-chloro-pyridin-2-yloxy) cyclohexyl]-4H,6H-2,3,5,10b-tetraaza-benzo[e]azulene-5-carboxylic acid tert-butyl ester according to general procedure VI. MS m/e: 430 (M+H) Example 75 trans-8-Chloro-l-[4-(5-chloro-pyridin-2-yloxy)-cyclohexyl]-5-methyl-5,6-dihydro-4H 30 2,3,5,10b-tetraaza-benzo[e]azulene The title compound was obtained from trans-8-chloro-1-[4-(5-chloro-pyridin-2-yloxy) cyclohexyl]-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene hydrochloride and paraformaldehyde according to general procedure VII. MS m/e: 444 (M+H) Example 76 WO 2010/060836 PCT/EP2009/065354 - 77 trans-8-Chloro- 1-[4-(2,6-dimethyl-pyrimidin-4-yloxy)-cyclohexyl] -4H,6H-2,3,5,1 Ob tetraaza-benzoazulene-5-carboxylic acid tert-butyl ester The title compound was obtained as white foam in 64% yield according to general procedure V. Hydrazide: trans-4-(2,6-Dimethyl-pyrimidin-4-yloxy)-cyclohexanecarboxylic acid hydrazide 5 Thiolactam: 7-Chloro-2-thioxo-1,2,3,5-tetrahydro-benzo[e][1 ,4]diazepine-4-carboxylic acid tert butyl ester MS ne: 525.5 MS (M+H+) Example 77 trans-8-Chloro-1-[4-(2,6-dimethyl-pyrimidin-4-yloxy)-cyclohexyl]-5,6-dihydro-4H 2,3,5,10b-tetraaza-benzoazulene hydrochloride 10 The title compound was obtained as white solid in quantitative yield from trans-8-chloro-1-[4 (2,6-dimethyl-pyrimidin-4-yloxy)-cyclohexyl]-4H,6H-2,3,5,10b-tetraaza-benzoazulene-5 carboxylic acid tert-butyl ester according to general procedure VI. MS m/e: 425 (M+H) Example 78 trans-8-Chloro-1-[4-(2,6-dimethyl-pyrimidin-4-yloxy)-cyclohexyl]-5-methyl-5,6-dihydro 15 4H-2,3,5,1 Ob-tetraaza-benzoazulene The title compound was obtained as white solid in 15% yield from trans- 8-chloro-1-[4-(2,6 dimethyl-pyrimidin-4-yloxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene hydrochloride and paraformaldehyde according to general procedure VII. MS m/e: 439 (M+H) Example 79 20 trans-8-Chloro-1-[4-(pyrimidin-2-yloxy)-cyclohexyl]-4H,6H-2,3,5,10b-tetraaza benzo[elazulene-5-carboxylic acid tert-butyl ester and Example 80 cis-8-Chloro-1-[4-(pyrimidin-2-yloxy)-cyclohexyl]-4H,6H-2,3,5,10b-tetraaza 25 benzo[elazulene-5-carboxylic acid tert-butyl ester trans-8-Chloro-1-[4-(pyrimidin-2-yloxy)-cyclohexyl]-4H,6H-2,3,5,10b-tetraaza benzo[e]azulene-5-carboxylic acid tert-butyl ester and cis-8-chloro-1-[4-(pyrimidin-2-yloxy) cyclohexyl]-4H,6H-2,3,5,10b-tetraaza-benzo[e]azulene-5-carboxylic acid tert-butyl ester were obtained after separation by flash-column chromatography according to general procedure V. 30 Hydrazide: cis/trans-4-(Pyrimidin-2-yloxy)-cyclohexanecarboxylic acid hydrazide (1:2) Thiolactam: 7-Chloro-2-thioxo- 1,2,3,5-tetrahydro-benzo[e] [ 1,4]diazepine-4-carboxylic acid tert butyl ester trans-8-Chloro-1-[4-(pyrimidin-2-yloxy)-cyclohexyl]-4H,6H-2,3,5,10b-tetraaza benzo[e]azulene-5-carboxylic acid tert-butyl ester was obtained as off-white solid in 38% yield.
WO 2010/060836 PCT/EP2009/065354 - 78 MS m/e: 497 (M+H') cis-8-Chloro-1-[4-(pyrimidin-2-yloxy)-cyclohexyl]-4H,6H-2,3,5,1 Ob-tetraaza-benzo[e]azulene 5-carboxylic acid tert-butyl ester was obtained as off-white solid in 8% yield. MS m/e: 497 (M+H) 5 Example 81 trans-8-Chloro-1-[4-(pyrimidin-2-yloxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b-tetraaza benzo[e]azulene The title compound was obtained as yellow solid in 73% yield from trans-8-chloro-1-[4 (pyrimidin-2-yloxy)-cyclohexyl]-4H,6H-2,3,5,10b-tetraaza-benzo[e]azulene-5-carboxylic acid 10 tert-butyl ester according to general procedure VI. MS m/e: 397 (M+H+) Example 82 trans-8-Chloro-5-methyl-1-[4-(pyrimidin-2-yloxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b tetraaza-benzo[e]azulene The title compound was obtained as white solid in 34% yield from trans-8-chloro-1-[4 15 (pyrimidin-2-yloxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene and paraformaldehyde according to general procedure VII. MS m/e: 411 (M+H+) Example 83 trans-8-Chloro-1-[4-(pyrazin-2-yloxy)-cyclohexyl]-4H,6H-2,3,5,10b-tetraaza benzo[e]azulene-5-carboxylic acid tert-butyl ester 20 The title compound was obtained as white solid in 70% yield according to general procedure V. Hydrazide: trans-4-(Pyrazin-2-yloxy)-cyclohexanecarboxylic acid hydrazide Thiolactam: 7-Chloro-2-thioxo- 1,2,3,5-tetrahydro-benzo[e] [ 1,4]diazepine-4-carboxylic acid tert butyl ester MS m/e: 497 (M+H) Example 84 25 trans-8-Chloro-1-[4-(pyrazin-2-yloxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5,1Ob-tetraaza benzo[e]azulene The title compound was obtained as yellow solid in 84% yield from trans-8-chloro-1-[4 (pyrazin-2-yloxy)-cyclohexyl]-4H,6H-2,3,5,10b-tetraaza-benzo[e]azulene-5-carboxylic acid tert butyl ester according to general procedure VI. MS m/e: 397 (M+H) 30 Example 85 trans- 8-Chloro-5-methyl-1-[4-(pyrazin-2-yloxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b tetraaza-benzo[e]azulene WO 2010/060836 PCT/EP2009/065354 - 79 The title compound was obtained as white solid in 45% yield from trans 8-chloro-1-[4-(pyrazin 2-yloxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5,1 Ob-tetraaza-benzo[e]azulene and paraformaldehyde according to general procedure VII. MS m/e: 411 (M+H ) Example 86 5 trans-8-Chloro-1-[4-(pyrimidin-4-yloxy)-cyclohexyl -4H,6H-2,3,5,10b-tetraaza benzo[e]azulene-5-carboxylic acid tert-butyl ester and Example 87 cis-8-Chloro-1-[4-(pyrimidin-4-yloxy)-cyclohexyl]-4H,6H-2,3,5,10b-tetraaza 10 benzo[e]azulene-5-carboxylic acid tert-butyl ester trans-8-Chloro-1-[4-(pyrimidin-4-yloxy)-cyclohexyl]-4H,6H-2,3,5,10b-tetraaza benzo[e]azulene-5-carboxylic acid tert-butyl ester and cis-8-chloro-1 -[4-(pyrimidin-4-yloxy) cyclohexyl]-4H,6H-2,3,5,10b-tetraaza-benzo[e]azulene-5-carboxylic acid tert-butyl ester were obtained after separation by flash-column chromatography according to general procedure V. 15 Hydrazide: cis/trans-4-(Pyrimidin-4-yloxy)-cyclohexanecarboxylic acid hydrazide (1:1) Thiolactam: 7-Chloro-2-thioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepine-4-carboxylic acid tert butyl ester trans-8-Chloro-1-[4-(pyrimidin-4-yloxy)-cyclohexyl]-4H,6H-2,3,5,10b-tetraaza benzo[e]azulene-5-carboxylic acid tert-butyl ester was obtained as white solid in 24% yield. 20 MS m/e: 497 (M+H ) cis-8-Chloro-1 -[4-(pyrimidin-4-yloxy)-cyclohexyl]-4H,6H-2,3,5, 1 Ob-tetraaza-benzo [e]azulene 5-carboxylic acid tert-butyl ester was obtained as white solid in 23% yield according to general procedure V. MS m/e: 497 (M+H) 25 Example 88 trans-8-Chloro-1-[4-(pyrimidin-4-yloxy)-cyclohexyll-5,6-dihydro-4H-2,3,5,10b-tetraaza benzo[elazulene hydrochloride The title compound was obtained as off-white solid in quantitative yield from trans-8-chloro- 1 [4-(pyrimidin-4-yloxy)-cyclohexyl]-4H,6H-2,3,5,10b-tetraaza-benzo[e]azulene-5-carboxylic 30 acid tert-butyl ester according to general procedure VI. MS m/e: 397 (M+H) Example 89 trans-8-Chloro-5-methyl-1-[4-(pyrimidin-4-yloxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b tetraaza-benzo[e]azulene WO 2010/060836 PCT/EP2009/065354 - 80 The title compound was obtained as white solid in 29% yield from trans-8-chloro-1-[4 (pyrimidin-4-yloxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5, 1 Ob-tetraaza-benzo [e]azulene hydrochloride and paraformaldehyde according to general procedure VII. MS m/e: 411 (M+H) 5 Example 90 cis-8-Chloro-1-[4-(pyrimidin-4-yoxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b-tetraaza benzo[e]azulene hydrochloride The title compound was obtained as white solid in quantitative yield from cis-8-chloro-1-[4 (pyrimidin-4-yloxy)-cyclohexyl]-4H,6H-2,3,5,10b-tetraaza-benzo[e]azulene-5-carboxylic acid 10 tert-butyl ester according to general procedure VI. MS m/e: 397 (M+H*) Example 91 cis-8-Chloro-5-methyl-1-[4-(pyrimidin-4-yloxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b tetraaza-benzo[e]azulene The title compound was obtained as white solid in 28% yield from cis-8-chloro-1-[4-(pyrimidin 15 4-yloxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene hydrochloride and paraformaldehyde according to general procedure VII. MS m/e: 411 (M+H) Example 92 trans-8-Chloro-1-[4-(pyridazin-3-yloxy)-cyclohexyl]-4H,6H-2,3,5,10b-tetraaza benzo[e]azulene-5-carboxylic acid tert-butyl ester 20 and Example 93 cis-8-Chloro-1-[4-(pyridazin-3-yloxy)-cyclohexyll-4H,6H-2,3,5,10b-tetraaza benzo[e]azulene-5-carboxylic acid tert-butyl ester trans-8-Chloro-1-[4-(pyridazin-3-yloxy)-cyclohexyl]-4H,6H-2,3,5,10b-tetraaza-benzo[e]azulene 25 5-carboxylic acid tert-butyl ester and cis-8-chloro-1-[4-(pyridazin-3-yloxy)-cyclohexyl]-4H,6H 2,3,5,1 Ob-tetraaza-benzo [e]azulene-5 -carboxylic acid tert-butyl ester were obtained after separation by flash-column chromatography according to general procedure V. Hydrazide: cis/trans-4-(Pyridazin-3-yloxy)-cyclohexanecarboxylic acid hydrazide (1:1) Thiolactam: 7-Chloro-2-thioxo- 1,2,3,5-tetrahydro-benzo[e] [ 1,4]diazepine-4-carboxylic acid tert 30 butyl ester trans-8-Chloro-1-[4-(pyridazin-3-yloxy)-cyclohexyl]-4H,6H-2,3,5, 1Ob-tetraaza-benzo[e]azulene 5-carboxylic acid tert-butyl ester was obtained as white solid in 19% yield. MS m/e: 497 (M+H+) WO 2010/060836 PCT/EP2009/065354 - 81 cis-8-Chloro-1-[4-(pyridazin-3-yloxy)-cyclohexyl]-4H,6H-2,3,5,1 Ob-tetraaza-benzo[e]azulene-5 carboxylic acid tert-butyl ester was obtained as white solid in 23% yield. MS m/e: 497 (M+Hv) Example 94 5 trans-8-Chloro-1-[4-(pyridazin-3-yloxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5,lOb-tetraaza benzo[e]azulene hydrochloride The title compound was obtained as off-white solid in quantitative yield from trans-8-cbloro-1 [4-(pyridazin-3-yloxy)-cyclohexyl]-4H,6H-2,3,5,10b-tetraaza-benzo[e]azulene-5-carboxylic acid tert-butyl ester according to general procedure VI. MS m/e: 397 (M+H+) 10 Example 95 trans-8-Chloro-5-methyl-1-[4-(pyridazin-3-yloxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b tetraaza-benzo[e]azulene The title compound was obtained as white solid in 11% yield from trans-8-chloro-1-[4 (pyridazin-3-yloxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene 15 hydrochloride and paraformaldehyde according to general procedure VII. MS m/e: 411 (M+H) Example 96 cis-8-Chloro-1-[4-(pyridazin-3-yloxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b-tetraaza benzo[e]azulene hydrochloride The title compound was obtained as off-white solid in quantitative yield from cis-8-chloro-1-[4 20 (pyridazin-3-yloxy)-cyclohexyl]-4H,6H-2,3,5,10b-tetraaza-benzo[e]azulene-5-carboxylic acid tert-butyl ester according to general procedure VI. MS m/e: 397 (M+H) Example 97 cis-8-Chloro-5-methyl-1-[4-(pyridazin-3-yloxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b tetraaza-benzo[e]azulene 25 The title compound was obtained as white solid in 3% yield from cis-8-chloro-1-[4-(pyridazin-3 yloxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene hydrochloride and paraformaldehyde according to general procedure VII. MS m/e: 411 (M+H) Example 98 trans-8-Chloro-1-[4-(3-fluoro-pyridin-2-yloxy)-cyclohexyl-5,6-dihydro-4H-2,3,5,10b 30 tetraaza-benzo[e]azulene The title compound was obtained as white solid in 78% yield over two steps according to general procedure V followed by treatment of the crude product under the conditions of general procedure VI. Hydrazide: trans-4-(3-Fluoro-pyridin-2-yloxy)-cyclohexanecarboxylic acid hydrazide WO 2010/060836 PCT/EP2009/065354 - 82 Thiolactam: 7-Chloro-2-thioxo- 1,2,3,5-tetrahydro-benzo [e] [1,4] diazepine-4-carboxylic acid tert butyl ester MS m/e: 414 (M+Hv) Example 99 5 trans-8-Chloro-1-[4-(3-fluoro-pyridin-2-yloxy)-cyclohexyl]-5-methyl-5,6-dihydro-4H 2,3,5,10b-tetraaza-benzo[e]azulene The title compound was obtained as white solid in 69% yield from trans-8-chloro-I-[4-(3-fluoro pyridin-2-yloxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene and paraformaldehyde according to general procedure VII. MS m/e: 428 (M+H) 10 Example 100 trans-8-Chloro-5-ethyl-1-[4-(3-fluoro-pyridin-2-yloxy)-cyclohexyl]-5,6-dihydro-4H 2,3,5,10b-tetraaza-benzo[e]azulene The title compound was obtained as white solid in 36% yield from trans-8-chloro-1-[4-(3-fluoro pyridin-2-yloxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene and 15 acetaldehyde according to general procedure VII. MS m/e: 442 (M+H+) Example 101 trans-8-Chloro-1-[4-(5-fluoro-pyridin-2-yloxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b tetraaza-benzo[e]azulene The title compound was obtained as white solid in 73% yield over two steps according to general 20 procedure V followed by treatment of the crude product under the conditions of general procedure VI. Hydrazide: trans-4-(5-Fluoro-pyridin-2-yloxy)-cyclohexanecarboxylic acid hydrazide Thiolactam: 7-Chloro-2-thioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepine-4-carboxylic acid tert butyl ester 25 MS m/e: 414 (M+Hv) Example 102 trans-8-Chloro-1-[4-(5-fluoro-pyridin-2-yloxy)-cyclohexyl-5-methyl-5,6-dihydro-4H 2,3,5,10b-tetraaza-benzo[elazulene The title compound was obtained as white solid in 61% yield from trans-8-chloro-1-[4-(5-fluoro 30 pyridin-2-yloxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene and paraformaldehyde according to general procedure VII. MS m/e: 428 (M+H-) Example 103 trans-8-Chloro-5-ethyl-1-[4-(5-fluoro-pyridin-2-yloxy)-cyclohexyl]-5,6-dihydro-4H 2,3,5,10b-tetraaza-benzo[e]azulene WO 2010/060836 PCT/EP2009/065354 - 83 The title compound was obtained as colorless waxy solid in 76% yield from trans-8-chloro-1-[4 (5-fluoro-pyridin-2-yloxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5,1 Ob-tetraaza-benzo[e]azulene and acetaldehyde according to general procedure VII. MS m/e: 442 (M+H ) Example 104 5 trans-8-Chloro-5-(2-fluoro-ethyl)-1-[4-(5-fluoro-pyridin-2-yloxy)-cyclohexyl]-5,6-dihydro 4H-2,3,5,1Ob-tetraaza-benzo[e] azulene A mixture of trans-8-chloro-1-[4-(5-fluoro-pyridin-2-yloxy)-cyclohexyl]-5,6-dihydro-4H 2,3,5,10b-tetraaza-benzo[e]azulene (0.10 g, 0.24 mmol) and potassium carbonate (67 mg, 0.48 mmol) in acetonitrile (1.2 ml) was treated with 1-bromo-2-fluoroethane (37 mg, 0.29 mmol) at 10 0 'C. The cooling bath was removed and the reaction mixture was heated at 70 'C over night. The mixture was filtered and concentrated in vacuo. Purification by flash column chromatography gave the title compound (17 mg, 15%) as white solid. MS m/e: 460 (M+H) Example 105 trans-8-Chloro-1-[4-(6-methyl-pyridin-2-yloxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b 15 tetraaza-benzo[e]azulene The title compound was obtained as white solid in 72% yield over two steps according to general procedure V followed by treatment of the crude product under the conditions of general procedure VI. Hydrazide: trans-4-(6-Methyl-pyridin-2-yloxy)-cyclohexanecarboxylic acid hydrazide 20 Thiolactam: 7-Chloro-2-thioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepine-4-carboxylic acid tert butyl ester MS m 1 e: 410 (M+H ) Example 106 trans-8-Chloro-5-methyl-1-[4-(6-methyl-pyridin-2-yloxy)-cyclohexyll-5,6-dihvdro-4H 25 2,3,5,10b-tetraaza-benzo[elazulene The title compound was obtained as white solid in 54% yield from trans-8-chloro-1-[4-(6 methyl-pyridin-2-yloxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene and paraformaldehyde according to general procedure VII. MS m/e: 424 (M)+H) Example 107 30 trans-8-Chloro-5-ethyl-1-[4-(6-methyl-pyridin-2-yloxy)-cyclohexyl]-5,6-dihydro-4H 2,3,5,10b-tetraaza-benzo[eazulene The title compound was obtained as colorless waxy solid in 62% yield from trans-8-chloro-1-[4 (5-fluoro-pyridin-2-yloxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene and acetaldehyde according to general procedure VII. MS m/e: 438 (M+H-) WO 2010/060836 PCT/EP2009/065354 - 84 Example 108 trans-8-Chloro-5-(2,2-difluoro-ethyl)-1-[4-(6-methyl-pyridin-2-vloxy)-cyclohexyl]-5,6 dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene A mixture of trans-8-chloro-1-[4-(6-methyl-pyridin-2-yloxy)-cyclohexyl]-5,6-dihydro-4H 5 2,3,5,1Ob-tetraaza-benzo[e]azulene (0.10 g, 0.24 mmol) and N,N-diisopropylethylamine (0.080 ml, 0.49 mmol) in dichloromethan (1 ml) was treated with trifluoro-methanesulfonic acid 2,2 difluoro-ethyl ester (63 mg, 0.29 mmol) at 0 'C. The cooling bath was removed after 30 min. and the reaction mixture was stirred at room temperature over night. The mixture was partitioned between aqueous staturated ammonium chloride solution (50 ml) and ethyl acetate (50 ml). The 10 aqueous layer was extracted with one 50-ml portion of ethyl acetate. The combined organic layers were washed with two 50-ml portions of a 1 M aqueous solution of sodium carbonate. The aqueous layers were each extracted with one 50-ml portion of ethyl acetate. The organic layers were dried over anhydrous sodium sulfate and concenrated in vacuo. Purification by flash column chromatography gave the title compound (98 mg, 85%) as white solid. 15 MS m/e: 474 (M+H ) Example 109 cis-8-Chloro-1-[4-(pyridin-2-yloxy)-cyclohexyl]-4H,6H-2,3,5,10b-tetraaza-benzo[e]azulene 5-carboxylic acid tert-butyl ester The title compound was obtained as light yellow solid in 79% yield according to general 20 procedure V. Hydrazide: cis-4-(Pyridin-2-yloxy)-cyclohexanecarboxylic acid hydrazide Thiolactam: 7-Chloro-2-thioxo- 1,2,3,5-tetrahydro-benzo[e] [ 1,4]diazepine-4-carboxylic acid tert butyl ester MS m/e: 496 (M+H) 25 Example 110 cis-8-Chloro-1-[4-(pyridin-2-vloxy)-cyclohexyll-5,6-dihydro-4H-2,3,5,10b-tetraaza benzo[elazulene The title compound was obtained as light yellow solid in 81% yield from cis-8-chloro-1-[4 (pyridin-2-yloxy)-cyclohexyl]-4H,6H-2,3,5, 1Ob-tetraaza-benzo[e]azulene-5-carboxylic acid tert 30 butyl ester hydrochloride and paraformaldehyde according to general procedure VI. MS m/e: 396 (M+H+ ) Example 111 cis-8-Chloro-5-methyl-1-[4-(pyridin-2-yloxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5,1Ob tetraaza-benzo[e]azulene WO 2010/060836 PCT/EP2009/065354 - 85 The title compound was obtained as white solid in 51% yield from cis-8-chloro-1-[4-(pyridin-2 yloxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5, 1 Ob-tetraaza-benzo [e]azulene and paraformaldehyde according to general procedure VII. MS m/e: 410 (M+H )
Claims (20)
1. The compound of the general formula I RR3 N NN N R2 wherein 5 R 1 is aryl or heteroaryl, unsubstituted or substituted with one or more substituents independently selected from A, R2 is H, C 1 - 1 2 -alkyl, unsubstituted or substituted with one or more OH, halo, cyano or Ci-12-alkoxy, 10 -(CH 2 )q-Ra, wherein Ra is phenyl or 5- or 6-membered heteroaryl, each unsubstituted or substituted with one or more substituents independently selected from A, -(CH 2 )rNR R, -C(O)-C 1 - 12 -alkyl, wherein C 1 - 1 2 -alkyl is unsubstituted or substituted with one or 15 more OH, halo, cyano or C 1 - 1 2 -alkoxy, -C(O)(CH 2 )qOC(O)-Ci- 12 -alkyl, -C(O)(CH 2 )qNR R , -C(O)O-C 1 - 1 2 -alkyl, wherein alkyl is unsubstituted or substituted with one or more OH, halo, cyano or C 1 - 12 -alkoxy, 20 -S(O) 2 -C 1 - 12 -alkyl, -S(O) 2 NR R , Ri and RH are each independently H, C 1 - 1 2 -alkyl, or form together with the nitrogen to which they are bound a 3- to 7-membered heterocycloalkyl containing one or two heteroatoms selected from N, 0 or S, which heterocycloalkyl is 25 unsubstituted or substituted by one or more substituents independently selected from B, q is 1, 2, 3 or 4, (9205908_1):JJP - 87 r is 2, 3 or 4, A is halo, cyano, OH, C 1 _ 7 -alkyl, halo-C 1 _ 7 -alkyl, or C 1 _ 7 -alkoxy, halo-C 1 _ 7 -alkoxy, or hydroxy-C 1 _ 7 -alkyl, B is oxo, halo, OH, C 1 _ 7 -alkyl or C 1 _ 7 -alkoxy, 5 R 3 is ClorF, or a pharmaceutically acceptable salt thereof.
2. The compound of formula I according to claim 1, wherein R is a monovalent cyclic aromatic hydrocarbon moiety consisting of a mono- or bicyclic aromatic ring, 10 a monovalent 5- or 6-membered aromatic monocyclic or 9- or 10-membered aromatic bicyclic ring containing from one to four ring heteroatoms selected from N, 0, or S, the remaining ring atoms being C, each unsubstituted or substituted with one or more substituents independently selected from A; and 15 A is is halo, cyano, OH, C1_ 7 -alkyl, halo-C1_ 7 -alkyl, C1_ 7 -alkoxy, halo-C1_ 7 -alkoxy, hydroxy-C1_7-alkyl.
3. The compound of formula I according to any one of claims 1 or 2, wherein R is a monovalent cyclic aromatic hydrocarbon moiety consisting of a mono-aromatic ring.
4. The compound of formula I according to any one of claims 1 or 2, wherein R 1 is naphthyl, 20 phenyl, pyrazinyl, pyridazinyl, pyridinyl or pyrimidinyl.
5. The compound of formula I according to any one of claims 1 or 2, wherein R 1 is phenyl, 4 fluoro-phenyl, 4-cyanophenyl, 4-trifluoromethyl-phenyl, 3-chloro-phenyl, 3-methoxy-phenyl, 3 cyano-phenyl, 3-methyl-phenyl, 3-t-butyl-phenyl, 3-trifluoromethyl-phenyl, 2-fluoro-phenyl, 2 cyano-phenyl, 2-methyl-phenyl, 3,5-di-fluoro-phenyl, naphth-2-yl, naphth-1-yl, pyridin-3-yl, 5 25 chloro-pyridin-3-yl, pyridin-2-yl, 6-chloro-pyridin-2-yl, 2,6-di-methyl-pyrimidin-4-yl, pyrimidin-2-yl, pyrazin-2-yl, pyridin-4-yl or pyridazin-3-yl.
6. The compound of formula I according to any one of claims 1 to 4, wherein R 1 is phenyl or pyridinyl.
7. The compound according to any one of claims 1 to 6, wherein (9205908_1):JJP - 88 R2 is H, C 1 - 1 2 -alkyl, unsubstituted or substituted with one or more OH or F, -(CH 2 )q-Ra, wherein Ra is phenyl or 5- or 6-membered heteroaryl and q is 1, 2, 3 or 4, preferably 1, 5 -C(O)-Ci- 12 -alkyl, -C(O)(CH 2 )qNRiRH, wherein Ri and R 1 are each independently H or C 1 - 1 2 -alkyl, preferably C 1 - 1 2 -alkyl, and q is 1, 2, 3 or 4, preferably 1, -C(O)O-C 1 - 12 -alkyl, -S(O) 2 -Ci- 12 -alkyl, or 10 -S(O) 2 NRiRH, wherein Ri and R 1 are each independently H or C 1 - 1 2 -alkyl, preferably C1- 1 2 -alkyl.
8. The compound according to any one of claims 1 to 7, wherein R2 is H, Ci-12-alkyl, unsubstituted or substituted with one or more OH, 15 -(CH2)q-Ra, wherein Ra is phenyl or 5- or 6-membered heteroaryl and q is 1, 2, 3 or 4, preferably 1, -C(O)-C1-12-alkyl, -C(O)(CH 2 )qNRR, wherein Ri and R 1 are each independently H or C1-12-alkyl, preferably C1-12-alkyl, and q is 1, 2, 3 or 4, preferably 1, 20 -C(O)O-C1-12-alkyl, -S(O)2-Ci-12-alkyl, or -S(O) 2 NRR, wherein Ri and R 1 are each independently H or C1-12-alkyl, preferably C1-12-alkyl.
9. The compound according to any one of claims 1 to 8, wherein R 2 is C1-12-alkyl. 25
10. The compound according to any one of claims 1 to 9, wherein R2 is 2 -hydroxy-ethyl, 2-fluoro-ethyl, 2,2-difluoro-ethyl, -C(O)CH 2 N(Me) 2 , -C(O)methyl, -CH 2 -pyridin-2-yl, -COO-t butyl, H, i-propyl, methyl, -S(O) 2 methyl or -S(O) 2 N(methyl) 2 .
11. The compound according to any one of claims 1 to 10, wherein R 2 is methyl.
12. The compound according to any one of claims 1 to 11, wherein R3 is Cl. 30
13. The compound according to any one of claims 1 to 12, wherein the compound is selected from (9205908_1):JJP - 89 trans-8-Chloro- 1-(4-phenoxy-cyclohexyl)-4H,6H-2,3,5, 1Ob-tetraaza-benzoazulene-5-carboxylic acid tert-butyl ester, trans-8-Chloro- 1-(4-phenoxy-cyclohexyl)-5 ,6-dihydro-4H-2,3,5, 1 Ob-tetraaza-benzoazulene hydrochloride, 5 trans-8-Chloro-5 -methyl-1-(4-phenoxy-cyclohexyl)-5 ,6-dihydro-4H-2,3,5, 1 Ob-tetraaza benzo[e]azulene, trans-1-[8-Chloro- 1-(4-phenoxy-cyclohexyl)-4H,6H-2,3,5, 1Ob-tetraaza-benzoazulen-5-yl] ethanone, trans-8-Chloro-5 -methanesulfonyl- 1-(4-phenoxy-cyclohexyl)-5,6-dihydro-4H-2,3,5, 1 Ob 10 tetraaza-benzoazulene, trans-2- [8-Chloro- 1-(4-phenoxy-cyclohexyl)-4H,6H-2,3,5, 1 Ob-tetraaza-benzoazulen-5 -yl] ethanol, trans-8-Chloro-5 -isopropyl- 1-(4-phenoxy-cyclohexyl)-5 ,6-dihydro-4H-2,3,5, 1 Ob-tetraaza benzoazulene, 15 trans-8-Chloro- 1-(4-phenoxy-cyclohexyl)-4H,6H-2,3,5, 1 Ob-tetraaza-benzoazulene-5 -sulfonic acid dimethylamide, trans-8-Chloro- 1-(4-phenoxy-cyclohexyl)-5 -pyridin-2-ylmethyl-5,6-dihydro-4H-2,3,5, 1 Ob tetraaza-benzoazulene, trans- 1-[8-Chloro- 1-(4-phenoxy-cyclohexyl)-4H,6H-2,3,5, 1Ob-tetraaza-benzoazulen-5-yl]-2 20 dimethylamino-ethanone, trans-8-Fluoro- 1-(4-phenoxy-cyclohexyl) -4H,6H-2,3,5, 1 Ob-tetraaza-benzo [e] azulene-5 carboxylic acid tert-butyl ester, trans-8-Fluoro-5 -methyl-1-(4-phenoxy-cyclohexyl)-5,6-dihydro-4H-2,3,5, 1Ob-tetraaza benzoazulene, 25 cis-8-Chloro- 1-(4-phenoxy-cyclohexyl)-4H,6H-2,3,5, 1Ob-tetraaza-benzoazulene-5-carboxylic acid tert-butyl ester, cis- 8-Chloro-5-methyl-1-(4-phenoxy-cyclohexyl)-5,6-dihydro-4H-2,3,5, 1Ob-tetraaza benzoazulene, trans-8-Chloro- 1-[4-(4-fluoro-phenoxy)-cyclohexyl]-4H,6H-2,3,5, 1Ob-tetraaza-benzoazulene-5 30 carboxylic acid tert-butyl ester, trans-8-Chloro- 1-[4-(4-fluoro-phenoxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5, 1Ob-tetraaza benzo[e]azulene hydrochloride, trans-8-Chloro- 1-[4-(4-fluoro-phenoxy)-cyclohexyl]-5-methyl-5,6-dihydro-4H-2,3,5, 1Ob tetraaza-benzoazulene, 35 trans-8-Chloro- 1-[4-(4-cyano-phenoxy)-cyclohexyl]-4H,6H-2,3,5, 1Ob-tetraaza-benzo[e]azulene 5-carboxylic acid tert-butyl ester, (9205908_1):JJP - 90 trans-4- [4-(8-Chloro-5-methyl-5,6-dihydro-4H-2,3,5, 1Ob-tetraaza-benzo[e] azulen- 1-yl) cyclohexyloxy] -benzonitrile, trans-8-Chloro- 1- [4-(4-trifluoromethyl-phenoxy)-cyclohexyl] -4H,6H-2,3,5, 1 Ob-tetraaza benzo[e]azulene-5-carboxylic acid tert-butyl ester, 5 trans-8-Chloro- 1- [4-(3 -chloro-phenoxy)-cyclohexyl] -4H,6H-2,3,5, 1 Ob-tetraaza-benzoazulene-5 carboxylic acid tert-butyl ester, trans-8-Chloro- 1- [4-(3-chloro-phenoxy)-cyclohexyl] -5-methyl-5,6-dihydro-4H-2,3,5, 1Ob tetraaza-benzoazulene, trans-8-Chloro- 1- [4-(3 -methoxy-phenoxy)-cyclohexyl] -4H,6H-2,3,5, 1 Ob-tetraaza-benzoazulene 10 5-carboxylic acid tert-butyl ester, trans-8-Chloro- 1- [4-(3 -methoxy-phenoxy)-cyclohexyl] -5,6-dihydro-4H-2,3,5, 1 Ob-tetraaza benzo[e]azulene hydrochloride, trans-8-Chloro- 1- [4-(3 -methoxy-phenoxy)-cyclohexyl] -5-methyl-5,6-dihydro-4H-2,3,5, 1 Ob tetraaza-benzoazulene, 15 trans-3- [4-(8-Chloro-5-methyl-5,6-dihydro-4H-2,3,5, 1Ob-tetraaza-benzoazulen- 1 -yl) cyclohexyloxy] -benzonitrile, trans-8-Chloro- 1-(4-m-tolyloxy-cyclohexyl)-4H,6H-2,3,5, 1 Ob-tetraaza-benzo [e] azulene-5 carboxylic acid tert-butyl ester, trans-8-Chloro- 1-(4-m-tolyloxy-cyclohexyl)-5 ,6-dihydro-4H-2,3,5, 1 Ob-tetraaza-benzo [e] azulene 20 hydrochloride, trans-8-Chloro-5 -methyl-1-(4-m-tolyloxy-cyclohexyl)-5 ,6-dihydro-4H-2,3,5, 1 Ob-tetraaza benzo[e]azulene, trans-1- [4-(3 -tert-Butyl-phenoxy)-cyclohexyl] - 8-chloro-4H,6H-2,3,5, 1 Ob-tetraaza benzo[e]azulene-5-carboxylic acid tert-butyl ester, 25 trans-8-Chloro- 1- [4-(2-fluoro-phenoxy)-cyclohexyl] -4H,6H-2,3,5, 1 Ob-tetraaza-benzo [e] azulene 5-carboxylic acid tert-butyl ester, trans-8-Chloro- 1- [4-(2-fluoro-phenoxy)-cyclohexyl] -5,6-dihydro-4H-2,3,5, 1 Ob-tetraaza benzo[e]azulene hydrochloride, trans-8-Chloro- 1- [4-(2-fluoro-phenoxy)-cyclohexyl] -5-methyl-5,6-dihydro-4H-2,3,5, 1Ob 30 tetraaza-benzo[e]azulene, trans-8-Chloro- 1- [4-(2-cyano-phenoxy)-cyclohexyl] -4H,6H-2,3,5, 1 Ob-tetraaza-benzoazulene-5 carboxylic acid tert-butyl ester, trans-2- [4-(8-Chloro-5,6-dihydro-4H-2,3,5, 1 Ob-tetraaza-benzo [e] azulen- 1 -yl)-cyclohexyloxy] benzonitrile hydrochloride, 35 trans-2- [4-(8-Chloro-5-methyl-5,6-dihydro-4H-2,3,5, 1Ob-tetraaza-benzoazulen- 1 -yl) cyclohexyloxy] -benzonitrile, (9205908_1):JJP - 91 trans-8-Chloro- 1-(4-o-tolyloxy-cyclohexyl)-4H,6H-2,3,5, 1Ob-tetraaza-benzoazulene-5 carboxylic acid tert-butyl ester, trans-8-Chloro-5 -methyl-1-(4-o-tolyloxy-cyclohexyl)-5,6-dihydro-4H-2,3,5,10b-tetraaza benzoazulene, 5 trans-8-Chloro- 1- [4-(3,5 -difluoro-phenoxy)-cyclohexyl] -4H,6H-2,3,5, 1Ob-tetraaza benzoazulene-5-carboxylic acid tert-butyl ester, trans-8-Chloro- 1- [4-(3,5 -difluoro-phenoxy)-cyclohexyl] -5-methyl-5,6-dihydro-4H-2,3,5, lOb tetraaza-benzoazulene, trans-8-Chloro- 1- [4-(naphthalen-2-yloxy)-cyclohexyl] -4H,6H-2,3,5, 1 Ob-tetraaza-benzoazulene 10 5-carboxylic acid tert-butyl ester, trans-8-Chloro-5 -methyl-1-[4-(naphthalen-2-yloxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5, 1Ob tetraaza-benzoazulene, trans-8-Chloro- 1- [4-(pyridin-3 -yloxy)-cyclohexyl] -4H,6H-2,3,5, 1 Ob-tetraaza-benzoazulene-5 carboxylic acid tert-butyl ester, 15 trans-8-Chloro-5-methyl- 1-[4-(pyridin-3-yloxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5, lOb-tetraaza benzoazulene, trans-8-Chloro- 1- [4-(5-chloro-pyridin-3-yloxy)-cyclohexyl] -4H,6H-2,3,5, lOb-tetraaza benzoazulene-5-carboxylic acid tert-butyl ester, trans-8-Chloro- 1- [4-(5 -chloro-pyridin-3 -yloxy)-cyclohexyl] -5-methyl-5,6-dihydro-4H-2,3,5, 1Ob 20 tetraaza-benzoazulene, trans-8-Chloro- 1- [4-(pyridin-2-yloxy)-cyclohexyl] -4H,6H-2,3,5, 1 Ob-tetraaza-benzoazulene-5 carboxylic acid tert-butyl ester, trans-8-Chloro- 1- [4-(pyridin-2-yloxy)-cyclohexyl] -5,6-dihydro-4H-2,3,5, 1 Ob-tetraaza benzoazulene hydrochloride, 25 trans-8-Chloro-5 -methyl-1-[4-(pyridin-2-yloxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5, 1Ob-tetraaza benzoazulene, trans-8-Chloro- 1- [4-(6-chloro-pyridin-2-yloxy)-cyclohexyl] -4H,6H-2,3,5, lOb-tetraaza benzo[e]azulene-5-carboxylic acid tert-butyl ester, trans-8-Chloro- 1- [4-(6-chloro-pyridin-2-yloxy)-cyclohexyl] -5-methyl-5,6-dihydro-4H-2,3,5, 1Ob 30 tetraaza-benzo[e]azulene, trans-8-Chloro- 1- [4-(5 -chloro-pyridin-2-yloxy)-cyclohexyl] -5,6-dihydro-4H-2,3,5, 1Ob-tetraaza benzo[e]azulene hydrochloride, trans-8-Chloro- 1- [4-(5 -chloro-pyridin-2-yloxy)-cyclohexyl] -5-methyl-5,6-dihydro-4H-2,3,5, 1Ob tetraaza-benzo[e]azulene, 35 trans-8-Chloro- 1- [4-(pyrimidin-2-yloxy)-cyclohexyl] -4H,6H-2,3,5, 1Ob-tetraaza benzo[e]azulene-5-carboxylic acid tert-butyl ester, (9205908_1):JJP - 92 cis-8-Chloro- 1-[4-(pyrimidin-2-yloxy)-cyclohexyl] -4H,6H-2,3,5, 1Ob-tetraaza-benzo[e] azulene 5-carboxylic acid tert-butyl ester, trans-8-Chloro-5-methyl- 1-[4-(pyrimidin-2-yloxy)-cyclohexyl] -5,6-dihydro-4H-2,3,5, 1Ob tetraaza-benzo[e]azulene, 5 trans-8-Chloro- 1- [4-(pyrazin-2-yloxy)-cyclohexyl] -4H,6H-2,3,5, 1 Ob-tetraaza-benzo [e] azulene 5-carboxylic acid tert-butyl ester, trans- 8-Chloro-5-methyl-1-[4-(pyrazin-2-yloxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b tetraaza-benzo[e]azulene, trans-8-Chloro- 1- [4-(pyrimidin-4-yloxy)-cyclohexyl] -4H,6H-2,3,5, 1 Ob-tetraaza 10 benzo[e]azulene-5-carboxylic acid tert-butyl ester, trans-8-Chloro-5-methyl- 1-[4-(pyrimidin-4-yloxy)-cyclohexyl] -5,6-dihydro-4H-2,3,5, 1Ob tetraaza-benzo[e]azulene, trans-8-Chloro- 1- [4-(pyridazin-3 -yloxy)-cyclohexyl] -4H,6H-2,3,5, 1 Ob-tetraaza-benzo [e] azulene 5-carboxylic acid tert-butyl ester, 15 cis- 8-Chloro- 1- [4-(pyridazin-3 -yloxy)-cyclohexyl] -4H,6H-2,3,5, 1 Ob-tetraaza-benzo [e] azulene-5 carboxylic acid tert-butyl ester, trans-8-Chloro-5-methyl- 1-[4-(pyridazin-3-yloxy)-cyclohexyl] -5,6-dihydro-4H-2,3,5, 1Ob tetraaza-benzo[e]azulene, cis- 8-Chloro- 1- [4-(pyridin-2-yloxy)-cyclohexyl] -4H,6H-2,3,5, 1 Ob-tetraaza-benzo [e] azulene-5 20 carboxylic acid tert-butyl ester , cis- 8-Chloro- 1- [4-(pyridin-2-yloxy)-cyclohexyl] -5,6-dihydro-4H-2,3,5, 1 Ob-tetraaza benzo[e]azulene , cis- 8-Chloro-5-methyl-1- [4-(pyridin-2-yloxy)-cyclohexyl] -5,6-dihydro-4H-2,3,5, 1 Ob-tetraaza benzo[e]azulene , 25 trans-8-Chloro- 1- [4-(3 -fluoro-pyridin-2-yloxy)-cyclohexyl] -5,6-dihydro-4H-2,3,5, 1 Ob-tetraaza benzo[e]azulene, trans-8-Chloro- 1- [4-(3-fluoro-pyridin-2-yloxy)-cyclohexyl] -5-methyl-5,6-dihydro-4H-2,3,5, 1Ob tetraaza-benzo[e]azulene, trans-8-Chloro- 1- [4-(5 -fluoro-pyridin-2-yloxy)-cyclohexyl] -5,6-dihydro-4H-2,3,5, 1 Ob-tetraaza 30 benzo[e]azulene trans-8-Chloro- 1- [4-(5-fluoro-pyridin-2-yloxy)-cyclohexyl] -5-methyl-5,6-dihydro-4H-2,3,5, 1Ob tetraaza-benzo[e]azulene, trans-8-Chloro- 1- [4-(6-methyl-pyridin-2-yloxy)-cyclohexyl] -5,6-dihydro-4H-2,3,5, 1 Ob-tetraaza benzo[e]azulene, 35 trans-8-Chloro-5 -(2,2-difluoro-ethyl)- 1- [4-(6-methyl-pyridin-2-yloxy)-cyclohexyl] -5,6-dihydro 4H-2,3,5,10b-tetraaza-benzo[e]azulene, (9205908_1):JJP - 93 trans-8-Chloro-5 -(2-fluoro-ethyl)- 1- [4-(5-fluoro-pyridin-2-yloxy)-cyclohexyl] -5,6-dihydro-4H 2,3,5,lOb-tetraaza-benzo[e]azulene, trans-8-Chloro-5-ethyl- 1- [4-(3-fluoro-pyridin-2-yloxy)-cyclohexyl] -5,6-dihydro-4H-2,3,5, lOb tetraaza-benzo [e] azulene, 5 trans-8-Chloro-5-ethyl- 1- [4-(5-fluoro-pyridin-2-yloxy)-cyclohexyl] -5,6-dihydro-4H-2,3,5, lOb tetraaza-benzo [e] azulene, trans-8-Chloro-5 -ethyl-1- [4-(6-methyl-pyridin-2-yloxy)-cyclohexyl] -5,6-dihydro-4H-2,3,5, lOb tetraaza-benzo[e]azulene, or trans-8-Chloro-5 -methyl-1- [4-(6-methyl-pyridin-2-yloxy)-cyclohexyl] -5,6-dihydro-4H 10 2,3,5,10b-tetraaza-benzo[e]azulene.
14. A process for the preparation of the compound of formula I according to any of claims 1 to 13, comprising the step of reacting a compound of formula II R 1 H N NH 2 0 I I with a compound of formula (III): H S N R N \R2 15 to obtain a compound of formula (I) wherein R , R 2 and R 3 are as defined in claim 1.
15. A compound formula I, whenever obtained by the process according to claim 14.
16. A compound of formula I according to any one of claims 1 to 13 for use as therapeutically active substance. 20
17. A compound of formula I according to any one of claims 1 to 13 for a use in the prevention or treatment of dysmenorrhea, male or female sexual dysfunction, hypertension, chronic heart failure, inappropriate secretion of vasopressin, liver cirrhosis, nephrotic syndrome, anxiety, (9205908_1):JJP - 94 depressive disorders, obsessive compulsive disorder, autistic spectrum disorders, schizophrenia, and aggressive behavior.
18. A pharmaceutical composition comprising a compound of formula I according to any one of claims 1 to 13. 5
19. Use of a compound of formula I according to any one of claims 1 to 13 for the preparation of a medicament for the prevention or treatment of dysmenorrhea, male or female sexual dysfunction, hypertension, chronic heart failure, inappropriate secretion of vasopressin, liver cirrhosis, nephrotic syndrome, anxiety, depressive disorders, obsessive compulsive disorder, autistic spectrum disorders, schizophrenia, and aggressive behavior. 10
20. A method for the therapeutic and/or prophylactic treatment of dysmenorrhea, male or female sexual dysfunction, hypertension, chronic heart failure, inappropriate secretion of vasopressin, liver cirrhosis, nephrotic syndrome, anxiety, depressive disorders, obsessive compulsive disorder, autistic spectrum disorders, schizophrenia, and aggressive behavior, which method comprises administering a compound according to any of claims 1-13 to a human being 15 or animal. F. Hoffmann-La Roche AG Patent Attorneys for the Applicant/Nominated Person SPRUSON & FERGUSON (9205908_1):JJP
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Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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Family Cites Families (20)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5521173A (en) | 1995-01-17 | 1996-05-28 | American Home Products Corporation | Tricyclic benzazepine vasopressin antagonists |
WO2000043398A2 (en) | 1999-01-19 | 2000-07-27 | Ortho-Mcneil Pharmaceutical, Inc. | Tricyclic benzodiazepines as vasopressin receptor antagonists |
TWI239333B (en) * | 2000-11-16 | 2005-09-11 | Hoffmann La Roche | Benzodiazepine derivatives as GABA A receptor modulators |
US7022699B2 (en) | 2001-04-12 | 2006-04-04 | Wyeth | Cyclohexenyl phenyl diazepines vasopressin and oxytocin receptor modulators |
GB0303852D0 (en) | 2003-02-19 | 2003-03-26 | Pfizer Ltd | Triazole compounds useful in therapy |
KR100840852B1 (en) | 2004-05-25 | 2008-06-23 | 화이자 프로덕츠 인크. | Tetraazabenzo[e]azulene derivatives and analogs thereof |
EA010888B1 (en) | 2004-05-25 | 2008-12-30 | Пфайзер Продактс, Инк. | Tetraazabenzo[e]azulene derivatives and analogs thereof |
EP1632494A1 (en) | 2004-08-24 | 2006-03-08 | Ferring B.V. | Vasopressin v1a antagonists |
US7456170B2 (en) | 2004-08-25 | 2008-11-25 | Pfizer Inc. | Triazolobenzodiazepines and their use as vasopressin antagonists |
JP2008539220A (en) | 2005-04-26 | 2008-11-13 | ファイザー・リミテッド | Triazole derivatives as vasopressin antagonists |
US20080234252A1 (en) | 2005-05-18 | 2008-09-25 | Pfizer Inc | Compounds Useful in Therapy |
ATE536356T1 (en) | 2007-01-12 | 2011-12-15 | Hoffmann La Roche | SPIROPIPERIDINE GLYCINAMIDE DERIVATIVES |
KR101159060B1 (en) * | 2008-04-09 | 2012-07-03 | 가부시키가이샤 구라레 | Laminate having gas barrier properties, and manufacturing method therefor |
CA2741018A1 (en) | 2008-11-13 | 2010-05-20 | F. Hoffmann-La Roche Ag | Spiro-5,6-dihydro-4h-2,3,5,10b-tetraaza-benzo[e]azulenes |
WO2010057795A1 (en) * | 2008-11-18 | 2010-05-27 | F. Hoffmann-La Roche Ag | Alkylcyclohexylethers of dihydrotetraazabenzoazulenes |
US8420633B2 (en) | 2010-03-31 | 2013-04-16 | Hoffmann-La Roche Inc. | Aryl-cyclohexyl-tetraazabenzo[e]azulenes |
US8461151B2 (en) | 2010-04-13 | 2013-06-11 | Hoffmann-La Roche Inc. | Aryl-/heteroaryl-cyclohexenyl-tetraazabenzo[e]azulenes |
US8492376B2 (en) | 2010-04-21 | 2013-07-23 | Hoffmann-La Roche Inc. | Heteroaryl-cyclohexyl-tetraazabenzo[e]azulenes |
US8481528B2 (en) | 2010-04-26 | 2013-07-09 | Hoffmann-La Roche Inc. | Heterobiaryl-cyclohexyl-tetraazabenzo[e]azulenes |
US8513238B2 (en) | 2010-05-10 | 2013-08-20 | Hoffmann-La Roche Inc. | Heteroaryl-cyclohexyl-tetraazabenzo[E]azulenes |
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